Preventive or therapeutic agent for pain associated with herpes zoster in acute phase

ABSTRACT

A P2X 4  receptor antagonist such as paroxetine, a diazepinedione derivative having the following formula (IX) is used as an agent for preventing or treating zoster-associated pain in acute phase: 
                         
wherein R 1  is hydrogen, a C 1-8  alkyl group, or the like;
         each of R 2  and R 3  is hydrogen, a C 1-8  alkyl group, or the like;   each of R 4  and R 5  is hydrogen or the like; and   W is a five-membered or six-membered heterocyclic ring optionally having one or more substituents and comprising one to four nitrogen atoms as the members of the ring.

FIELD OF THE INVENTION

The present invention relates to an agent for preventing or treatingzoster-associated pain in acute phase.

BACKGROUND OF THE INVENTION

Herpes zoster is a viral disease caused by a varicella zoster virus(VZV). Initial infection of VZV is usually in childhood to causevaricella. The infected host may acquire humoral and cellular immunitiesagainst VZV to cease proliferation of virus. At the same time, virus maypartly be incorporated into the peripheral end of sensory nerve fibersdistributed in the skin, ascend the sensory nerve fiber along aretrograde axonal flow, and cause latent infection in ganglion. When thespecific cellular immunity against VZV is lowed in the host, virus isreactivated to develop the syndrome of the herpes zoster. Thereactivated virus descends the sensory nerve fiber along an antegradeaxonal flow to reach the skin and cause zonary exanthema. The exanthemais naturally healed generally within about three weeks.

The zoster-associated pain is generally classified into an acute phasepain and a chronic phase pain. The chronic phase pain is a generalproblem, which continues over a long term after healing the exanthema.The chronic phase pain is called postherpetic neuralgia, which isconsidered as neuropathic pain caused by neural degeneration in centraland peripheral nervous systems (Non-patent documents 1, 2, and 3).Tricyclic antidepressant, opioid, antiepileptic drugs or the like areused for the present to treat postherpetic neuralgia, and theirtreatment effects are reported.

On the other hand, the acute phase pain is prodrome or pain in an acutephase, which causes neuralgia-like pain several days before developmentof exanthema. It includes neuritis pain caused by proliferated virus andinflammatory pain within the area of exanthema. The area of exanthemacan be the center of algesthesia, and pain runs along the nerve. Thestrength of the pain widely ranges from lightly stimulated symptom toheavy pain losing sleep at night. A HSV-1 infected rat has been used asa herpes zoster model. It has been confirmed that the rat can bespontaneously excited without inflammatory syndrome in the spinalposterior root ganglion. It is suggested that acute phase pain may beexpressed with spontaneous hypersthenia of the primary neuron cell body(Non-patent document 4).

The acute phase of herpes zoster is treated for the present by using acombination of antiviral agent such as Valaciclovir, Aciclovir,Famciclovir or the like with an analgesic such as NSAIDs. The NSAIDs hasan effect on inflammatory pain, but no effect on neuritis-like pain.Further, whole body administration of opioid is sometimes used. It hasbeen known that the above-mentioned pharmacotherapy can have anaccelerating effect of healing exanthema, and show a partial effect onacute phase pain, but it cannot suppress the pain completely. Therefore,nerve block treatments, such as epidural block, stellate block,peripheral nerve block has been used in the case that the exanthema andpain are serious (Non-patent document 5). For the reasons mentionedabove, it has been desired to develop a method of treating acute phaseof herpes zoster pain in view of QOL of the herpes zoster patients.

The present inventors have found that paroxetine, a diazepinedionederivative or the like having a P2X₄ receptor antagonism can be used asan agent for preventing or treating neuropathic pain, and filed patentapplications (Patent documents 1 and 2).

The patent documents, however, do not clearly describe that theabove-mentioned compounds are available as an agent for preventing ortreating zoster-associated pain in acute phase.

PRIOR ART DOCUMENTS Patent Documents

Patent document 1: WO 2008/020651

Patent document 2: WO 2010/093061

Non-Patent Documents

Non-patent document 1: Oaklander A L., Pain, 2001, 92:139-145

Non-patent document 2: Watson C P, et al., Pain, 1991, 44:105-117

Non-patent document 3: Rowbotham M C, et al., Neuro-biol Dis, 1996,3:205-214

Non-patent document 4: Fleetwood-Walker S M, et al., J Gen Virol., 1999,80:2433-2436

Non-patent document 5: Kazushige Kawamura et al., the Progress ofMedicine, 2007, Vol. 223, No 9:40-42

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

It is the object of the invention to provide an agent for preventing ortreating zoster-associated pain in acute phase.

Means for Solving the Problems

The present inventors have found that P2X₄ receptor antagonist such asparoxetine, a diazepinedione derivative or the like can be used as anagent for preventing or treating zoster-associated pain in acute phase,and completed the present invention.

The present invention relates to an agent for preventing or treatingzoster-associated pain in acute phase containing P2X₄ receptorantagonist as an active ingredient.

The invention also relates to an agent for preventing or treatingzoster-associated pain in acute phase containing a compound having thefollowing formula (I) or a pharmacologically acceptable salt thereof asan active ingredient:

wherein R¹ is a halogen atom; and

R² is hydrogen, a halogen atom, nitro, cyano, —C(O)—OR³, —C(O)—NR⁴R⁵,—SO₂—OR³, —SO₂—NR⁴R⁵, wherein each of R³, R⁴, and R⁵ is hydrogen or aC₁₋₆ alkyl group; or in the alternative

R¹ is hydrogen; and

R² is a halogen atom, nitro, cyano, —C(O)—OR³, —C(O)—NR⁴R⁵, —SO₂—OR³,—SO₂—NR⁴R⁵, wherein each of R³, R⁴, and R⁵ is hydrogen or a C₁₋₆ alkylgroup.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing a compound having thefollowing formula (Ia) or a pharmacologically acceptable salt thereof asan active ingredient:

wherein R¹ is chloro or bromo; and

R² is hydrogen, chloro, bromo, nitro, or cyano; or in the alternative

R¹ is hydrogen; and

R² is chloro, bromo, nitro, or cyano.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing a compound having thefollowing formula (II) or a pharmacologically acceptable salt thereof asan active ingredient:

wherein R is a C₁₋₄ alkyl group, a C₂₋₄ alkynyl group, phenyl optionallyhaving one or more substituents selected from the group consisting of alower alkyl group, an alkylthio group, an alkoxy group, a halogen atom,nitro, an acylamino group, methylsulfonyl, and methylenedioxy, ortetrahydronaphthyl;

R¹ is hydrogen; and

X is hydrogen, a C₁₋₄ alkyl group, a trifluoroalkyl group, hydroxyl, ahalogen atom, methylthio, or an arylalkoxy group.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing a selective serotoninreuptake inhibitor as an active ingredient.

The invention further relates to An agent for preventing or treatingzoster-associated pain in acute phase containing an agent selected fromthe group consisting of imipramine, nortriptyline, amitriptyline,desipramine, doxepin, fluoxetine, fluvoxamine, citalopram, and apharmacologically acceptable salt thereof as an active ingredient.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing a compound having thefollowing formula (III) or a pharmacologically acceptable salt thereofas an active ingredient:

wherein X is S or CH₂;

Y is O, S, or NH;

R¹ is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkyl group having one ormore halogen atoms, an aralkyl group comprising a C₁₋₆ alkyl moiety anda C₆₋₁₀ aryl moiety, a C₂₋₈ alkenyl group, carboxymethyl, or analkoxycarbonylmethyl group comprising a C₁₋₈ alkoxy moiety;

each of R² and R³ independently is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈alkoxy group, a C₁₋₈ alkyl group having one or more halogen atoms, aC₁₋₈ alkoxy group having one or more halogen atoms, a halogen atom,amino, carboxyl, hydroxyl, nitro, cyano, a C₂₋₈ acyl group, a C₆₋₁₀ arylgroup, or a five-membered or six-membered heterocyclic group;

each of R⁴ and R⁵ independently is hydrogen, a C₁₋₈ alkyl group, or aC₁₋₈ alkyl group having one or more halogen atoms; and

the double line consisting of a broken line and a solid line is a singlebond or a double bond.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing a compound having thefollowing formula (IV) or a pharmacologically acceptable salt thereof asan active ingredient:

wherein X^(a) is O, S, or NH;

R^(1a) is hydroxyl, tetrazolyl, N(R^(5a))(R^(6a)), a C₂₋₈ alkenyl group,a C₂₋₈ alkynyl group, a C₁₋₈ alkyl group having one or more halogenatoms, a C₁₋₈ alkoxy group having one or more halogen atoms, or a C₆₋₁₀aryl group, wherein R^(5a) is hydrogen or a C₁₋₈ alkyl group, and R^(6a)is hydrogen, a C₁₋₈ alkyl group, or a C₂₋₈ acyl group;

each of R^(2a) and R^(3a) independently is hydrogen, a C₁₋₈ alkyl group,or a C₁₋₈ alkyl group having one or more halogen atoms; and

R^(4a) is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈alkyl group having one or more halogen atoms, a halogen atom, hydroxyl,nitro, amino, carboxyl, tetrazolyl, cyano, a C₆₋₁₀ aryl group, or afive-membered or six-membered heterocyclic group.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing a compound having thefollowing formula (IVa) or a pharmacologically acceptable salt thereofas an active ingredient:

wherein X^(b) is O, S, or NH;

R^(1b) is a halogen atom, hydroxyl, tetrazolyl, N(R^(5b))(R^(6b)), aC₂₋₈ alkenyl group, a C₂₋₈ alkynyl group, a C₁₋₈ alkyl group having oneor more halogen atoms, a C₁₋₈ alkoxy group having one or more halogenatoms, or a C₆₋₁₀ aryl group, wherein R^(5b) is hydrogen or a C₁₋₈ alkylgroup, and R^(6b) is hydrogen, a C₁₋₈ alkyl group, or a C₂₋₈ acyl group;

each of R^(2b) and R^(3b) independently is hydrogen, a C₁₋₈ alkyl group,or a C₁₋₈ alkyl group having one or more halogen atoms;

R^(4b) is hydrogen, a C₁₋₈ alkyl group, an alkoxy group, a C₁₋₈ alkylgroup having one or more halogen atoms, a halogen atom, hydroxyl, nitro,amino, carboxyl, tetrazolyl, cyano, a C₆₋₁₀ aryl group, or afive-membered or six-membered heterocyclic group; and

R^(7b) is a C₁₋₈ alkyl group.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing a compound having thefollowing formula (IVb) or a pharmacologically acceptable salt thereofas an active ingredient:

wherein X^(c) is O, S, or NH;

R^(1c) is hydrogen, a halogen atom, a C₁₋₈ alkyl group, a C₁₋₈ alkoxygroup, hydroxyl, tetrazolyl, N(R^(5c))(R^(6c)), a C₂₋₈ alkenyl group, aC₂₋₈ alkynyl group, a C₁₋₈ alkyl group having one or more halogen atoms,a C₁₋₈ alkoxy group having one or more halogen atoms, or a C₆₋₁₀ arylgroup, wherein R^(5c) is hydrogen or a C₁₋₈ alkyl group, and R^(6c) ishydrogen, a C₁₋₈ alkyl group, or a C₂₋₈ acyl group;

each of R^(2c) and R^(3c) independently is hydrogen, a C₁₋₈ alkyl group,or a C₁₋₈ alkyl group having one or more halogen atoms;

R^(4c) is hydrogen, a C₁₋₈ alkyl group, an alkoxy group, a C₁₋₈ alkylgroup having one or more halogen atoms, a halogen atom, hydroxyl, nitro,amino, carboxyl, tetrazolyl, cyano, a C₆₋₁₀ aryl group, or afive-membered or six-membered heterocyclic group;

R^(7c) is hydrogen or a C₁₋₈ alkyl group; and

R^(8c) is hydrogen, a C₁₋₈ alkyl group, or a C₂₋₈ acyl group.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing a compound having thefollowing formula (V) or a pharmacologically acceptable salt thereof asan active ingredient:

wherein X is O, S, or NH;

Y is N or NR⁶, wherein R⁶ is hydrogen or a C₁₋₈ alkyl group;

R¹ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkylgroup having one to three halogen atoms, or an alkyl group havingphenyl;

R² is a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group havingone to three halogen atoms, hydroxyl, nitro, amino, carboxyl,tetrazolyl, or cyano;

R³ is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkylgroup having one to three halogen atoms, a halogen atom, hydroxyl,nitro, amino, carboxyl, tetrazolyl, or cyano;

each of R⁴ and R⁵ independently is hydrogen, a C₁₋₈ alkyl group, or aC₁₋₈ alkyl group having one to three halogen atoms;

m is 1 or 2;

when Y is N, the double line consisting of a solid line and a brokenline is a double bond; and

when Y is NR⁶, the double line consisting of a solid line and a brokenline is a single bond.

The invention further relates to An agent for preventing or treatingzoster-associated pain in acute phase containing a compound having thefollowing formula (Va) or a pharmacologically acceptable salt thereof asan active ingredient:

wherein R¹¹ is hydrogen or a C₁₋₈ alkyl group;

R²¹ is a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl grouphaving one to three halogen atoms, or hydroxyl; and

R³¹ is hydrogen or a halogen atom.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing a compound having thefollowing formula (VI) or a pharmacologically acceptable salt thereof asan active ingredient:

wherein A is an aryl group optionally having one or more substituents ora heterocyclic group optionally having one or more substituents;

B is an aryl group optionally having one or more substituents or aheterocyclic group optionally having one or more substituents;

X is a C₁₋₅ alkylene group or a bond;

Y is a C₁₋₅ alkylene optionally comprising a double bond;

Z is O, S, N(R⁵), or a bond, wherein R⁵ is hydrogen or a C₁₋₈ alkylgroup;

each of R¹, R², and R³ independently is hydrogen, a C₁₋₈ alkyl group, ora C₁₋₈ alkyl group having one to three halogen atoms;

R⁴ is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkyl group having one tothree halogen atoms, a three-membered to seven-membered cycloalkylgroup, or a C₁₋₈ alkyl group having a three-membered to seven-memberedcycloalkyl group; and

each of n and m independently is 1 or 2;

provided that the substituent of the aryl group represented by A is notan alkyl group when X is a bond.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing a compound having thefollowing formula (VIa) or a pharmacologically acceptable salt thereofas an active ingredient:

wherein A¹ is phenyl or thienyl, each of which optionally has one tothree substituents selected from the group consisting of a halogen atom,a C₁₋₈ alkyl group having one to three halogen atoms, nitro, cyano,hydroxyl, amino, a C₁₋₈ alkylamino group, a C₂₋₁₆ dialkylamino group, aC₂₋₈ acylamino group, a C₁₋₈ alkoxy group, a C₁₋₈ alkoxy group havingone to three halogen atoms, an aryl group, and a heterocyclic group;

B¹ is an aryl group optionally having one or more substituents or aheterocyclic group optionally having one or more substituents;

Y¹ is a C₁₋₅ alkylene chain optionally comprising a double bond;

Z¹ is O, S, N(R⁷), or a bond, wherein R⁷ is hydrogen or a C₁₋₈ alkylgroup; and

R⁶ is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkyl group having one tothree halogen atoms, or a three-membered to seven-membered cycloalkylgroup.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing a compound having thefollowing formula (VIb) or a pharmacologically acceptable salt thereofas an active ingredient:

wherein A² is phenyl or thienyl, each of which optionally has one tothree substituents selected from the group consisting of a halogen atom,a C₁₋₈ alkyl group having one to three halogen atoms, nitro, cyano,acetylamino, a C₁₋₈ alkoxy group, a C₁₋₈ alkoxy group having one tothree halogen atoms, an aryl group, and a heterocyclic group;

B² is phenyl, naphthyl, benzofuranyl, 1,3-benzo[d]dioxolyl, quinolyl,indolyl, benzothienyl, thienyl, or pyridyl, each of which optionally hasone to three substituents selected from the group consisting of ahalogen atom, a C₁₋₈ alkyl group, a C₁₋₈ alkyl group having one to threehalogen atoms, nitro, cyano, hydroxyl, amino, a C₂₋₈ acylamino group, aC₁₋₈ alkoxy group, a C₁₋₈ alkoxy group having one to three halogenatoms, a C₆₋₁₂ aryloxy group, sulfamoyl, a C₁₋₈ alkylsulfamoyl group,and a C₂₋₁₆ dialkylsulfamoyl group;

Z² is O, S, or NH; and

R⁸ is hydrogen or a C₁₋₈ alkyl group.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing a compound having thefollowing formula (VII) or a pharmacologically acceptable salt thereofas an active ingredient:

wherein B is an aryl group optionally having one or more substituents ora heterocyclic group optionally having one or more substituents;

Y is a C₁₋₅ alkylene optionally comprising a double bond;

Z is O, S, N(R⁵), or a bond, wherein R⁵ is hydrogen or a C₁₋₈ alkylgroup;

each of R¹, R², and R³ independently is hydrogen, a C₁₋₈ alkyl group, ora C₁₋₈ alkyl group having one to three halogen atoms;

R⁴ is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkyl group having one tothree halogen atoms, a three-membered to seven-membered cycloalkylgroup, or a C₁₋₈ alkyl group having a three-membered to seven-memberedcycloalkyl group;

each of P and Q independently is hydrogen, a halogen atom, a C₁₋₈ alkylgroup, a C₁₋₈ alkyl group having one to three halogen atoms, nitro,cyano, hydroxyl, amino, a C₁₋₈ alkylamino group, a C₂₋₁₆ dialkylaminogroup, a C₂₋₈ acylamino group, a C₁₋₈ alkoxy group, a C₁₋₈ alkoxy grouphaving one to three halogen atoms, or a heterocyclic group;

W is a C₁₋₈ alkyl group or a three-membered to seven-membered cycloalkylgroup; or

P and W are combined to form propylene or tetramethylene when P and Ware placed at 2- and 3-positions or 3- and 4-positions of phenyl; and

each of n and m independently is 1 or 2.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing a compound having thefollowing formula (VIII) or a pharmacologically acceptable salt thereofas an active ingredient:

wherein R¹ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈alkyl group having one to three halogen atoms, or a C₁₋₃ alkyl grouphaving phenyl;

R² is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkylgroup having one to three halogen atoms, a C₁₋₈ alkoxy group having oneto three halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino, aC₁₋₈ alkylamino group, a C₂₋₈ dialkylamino group, a C₂₋₈ acylaminogroup, a C₂₋₈ acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonylgroup comprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthiogroup, a C₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, orsulfamoyl;

R³ is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkylgroup having one to three halogen atoms, a C₁₋₈ alkoxy group having oneto three halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino,carboxyl, a C₂₋₈ acyl group, or an alkoxycarbonyl group comprising aC₁₋₈ alkoxy moiety; and

-   -   each of R⁴ and R⁵ independently is hydrogen, a C₁₋₈ alkyl group,        or a C₁₋₈ alkyl group having one to three halogen atoms.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing a compound having thefollowing formula (IX) or a pharmacologically acceptable salt thereof asan active ingredient:

wherein R¹ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈alkyl group having one to three halogen atoms, or a C₁₋₃ alkyl grouphaving phenyl;

each of R² and R³ independently is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈alkoxy group, a C₁₋₈ alkyl group having one to three halogen atoms, aC₁₋₈ alkoxy group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, a C₂₋₈dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈ acylamino grouphaving one to three halogen atoms, a C₁₋₈ alkylsulfonylamino group,carboxyl, a C₂₋₈ acyl group, an alkoxycarbonyl group comprising a C₁₋₈alkoxy moiety, carbamoyl, a C₁₋₈ alkylthio group, a C₁₋₈ alkylsulfinylgroup, a C₁₋₈ alkylsulfonyl group, or sulfamoyl;

each of R⁴ and R⁵ independently is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈alkyl group having one to three halogen atoms, or a C₁₋₃ alkyl grouphaving phenyl; and

W is a five-membered or six-membered heterocyclic ring optionally havingone or more substituents and comprising one to four nitrogen atoms asthe members of the ring.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dionesodium salt as an active ingredient.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing paroxetine or apharmacologically acceptable salt thereof as an active ingredient.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing a diazepine derivativehaving the following formula (X) or a pharmacologically acceptable saltthereof as an active ingredient:

wherein each of R¹ and R² independently is hydrogen, a C₁₋₈ alkyl group,a C₂₋₈ alkenyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having oneto three halogen atoms, a C₁₋₈ alkoxy group having one to three halogenatoms, a halogen atom, hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylaminogroup, a C₂₋₈ dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonylgroup comprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthiogroup, a C₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, orsulfamoyl;

R³ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkylgroup having one to three halogen atoms, or a C₁₋₃ alkyl group havingphenyl;

each of R⁴ and R⁵ independently is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈alkyl group having one to three halogen atoms, a halogen atom, hydroxyl,nitro, cyano, amino, or a C₁₋₃ alkyl group having phenyl;

R⁶ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxygroup, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈alkoxy group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, a C₂₋₈dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈ acylamino grouphaving one to three halogen atoms, a C₁₋₈ alkylsulfonylamino group,carboxyl, a C₂₋₈ acyl group, an alkoxycarbonyl group comprising a C₁₋₈alkoxy moiety, carbamoyl, a C₁₋₈ alkylthio group, a C₁₋₈ alkylsulfinylgroup, a C₁₋₈ alkylsulfonyl group, sulfamoyl, phenyl optionally havingone or more substituents, or a heterocyclic group optionally having oneor more substituents;

the ring shown below is a five-membered to eight-membered non-aromaticring optionally comprising one or two heteroatoms selected from N, S,and O, and being condensed with the benzene ring at 1- and 2-positionsof the benzene ring;

the ring shown below is an aromatic ring selected from the groupconsisting of benzene ring, naphthalene ring, thiophene ring, pyridinering, pyrimidine ring, indole ring, indazole ring, benzotriazole ring,benzisoxazole ring, benzimidazole ring, and quinoline ring;

Z is O or S;

when X is N, Y is C═O or C═S, and the double line consisting of a solidline and a broken line is a single bond; and

when X is C, Y is N, and the double line consisting of a solid line anda broken line is a double bond.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing a diazepine derivativehaving the following formula (Xa) or a pharmacologically acceptable saltthereof as an active ingredient:

wherein each of R¹¹ and R¹² independently is hydrogen, a C₁₋₈ alkylgroup, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl grouphaving one to three halogen atoms, a C₁₋₈ alkoxy group having one tothree halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino, aC₁₋₈ alkylamino group, a C₂₋₈ dialkylamino group, a C₂₋₈ acylaminogroup, a C₂₋₈ acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonylgroup comprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthiogroup, a C₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, orsulfamoyl;

R¹³ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkylgroup having one to three halogen atoms, or a C₁₋₃ alkyl group havingphenyl;

each of R¹⁴ and R¹⁵ independently is hydrogen, a C₁₋₈ alkyl group, aC₁₋₈ alkyl group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, or a C₁₋₃ alkyl group having phenyl;

R¹⁶ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxygroup, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈alkoxy group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, a C₂₋₈dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈ acylamino grouphaving one to three halogen atoms, a C₁₋₈ alkylsulfonylamino group,carboxyl, a C₂₋₈ acyl group, an alkoxycarbonyl group comprising a C₁₋₈alkoxy moiety, carbamoyl, a C₁₋₈ alkylthio group, a C₁₋₈ alkylsulfinylgroup, a C₁₋₈ alkylsulfonyl group, sulfamoyl, phenyl optionally havingone or more substituents, or a heterocyclic group optionally having oneor more substituents;

the ring shown below is a five-membered to eight-membered non-aromaticring optionally comprising one or two heteroatoms selected from N, S,and O, and being condensed with the benzene ring at 1- and 2-positionsof the benzene ring;

the ring shown below is an aromatic ring selected from the groupconsisting of benzene ring, naphthalene ring, thiophene ring, pyridinering, pyrimidine ring, indole ring, indazole ring, benzotriazole ring,benzisoxazole ring, benzimidazole ring, and quinoline ring; and

each of Z¹ and Z² independently is O or S.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing a diazepine derivativehaving the following formula (Xb) or a pharmacologically acceptable saltthereof as an active ingredient:

wherein each of R²¹ and R²² independently is hydrogen, a C₁₋₈ alkylgroup, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl grouphaving one to three halogen atoms, a C₁₋₈ alkoxy group having one tothree halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino, aC₁₋₈ alkylamino group, a C₂₋₈ dialkylamino group, a C₂₋₈ acylaminogroup, a C₂₋₈ acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonylgroup comprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthiogroup, a C₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, orsulfamoyl;

R²³ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkylgroup having one to three halogen atoms, or a C₁₋₃ alkyl group havingphenyl;

each of R²⁴ and R²⁵ independently is hydrogen, a C₁₋₈ alkyl group, aC₁₋₈ alkyl group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, or a C₁₋₃ alkyl group having phenyl;

R²⁶ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxygroup, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈alkoxy group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, a C₂₋₈dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈ acylamino grouphaving one to three halogen atoms, a C₁₋₈ alkylsulfonylamino group,carboxyl, a C₂₋₈ acyl group, an alkoxycarbonyl group comprising a C₁₋₈alkoxy moiety, carbamoyl, a C₁₋₈ alkylthio group, a C₁₋₈ alkylsulfinylgroup, a C₁₋₈ alkylsulfonyl group, sulfamoyl, phenyl optionally havingone or more substituents, or a heterocyclic group optionally having oneor more substituents; and

p is 0 or 1.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing a diazepine derivativehaving the following formula (XI) or a pharmacologically acceptable saltthereof as an active ingredient:

wherein R¹ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈alkoxy group, a C₁₋₈ alkyl group having one to three halogen atoms, aC₁₋₈ alkoxy group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, a C₂₋₈dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈ acylamino grouphaving one to three halogen atoms, a C₁₋₈ alkylsulfonylamino group,carboxyl, a C₂₋₈ acyl group, an alkoxycarbonyl group comprising a C₁₋₈alkoxy moiety, carbamoyl, a C₁₋₈ alkylthio group, a C₁₋₈ alkylsulfinylgroup, a C₁₋₈ alkylsulfonyl group, or sulfamoyl;

R² is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkylgroup having one to three halogen atoms, or a C₁₋₃ alkyl group havingphenyl;

each of R³ and R⁴ independently is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈alkyl group having one to three halogen atoms, a halogen atom, hydroxyl,nitro, cyano, amino, or a C₁₋₃ alkyl group having phenyl;

R⁵ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxygroup, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈alkoxy group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, a C₁₋₅alkylamino group having one to five halogen atoms, a C₂₋₈ dialkylaminogroup, a C₂₋₈ acylamino group, a C₂₋₈ acylamino group having one tothree halogen atoms, a C₁₋₈ alkylsulfonylamino group, carboxyl, a C₂₋₈acyl group, an alkoxycarbonyl group comprising a C₁₋₈ alkoxy moiety,carbamoyl, a C₁₋₈ alkylthio group, a C₁₋₈ alkylsulfinyl group, a C₁₋₈alkylsulfonyl group, sulfamoyl, phenyl optionally having one or moresubstituents, or a heterocyclic group optionally having one or moresubstituents;

X is C or N;

-   -   the ring shown below is a heterocyclic ring selected from the        group consisting of thiophene ring, pyridine ring, pyrimidine        ring, quinoline ring, indole ring, indoline ring, benzimidazole        ring, indazole ring, benzisoxazole ring, and benzotriazole ring,        and the ring is combined with X at the carbon atom contained in        the heterocyclic ring as the member of the ring

Z is O or S;

when X is N, Y is C═O or C═S, and the double line consisting of a solidline and a broken line is a single bond; and

when X is C, Y is N, and the double line consisting of a solid line anda broken line is a double bond.

The invention further relates to an agent for preventing or treatingzoster-associated pain in acute phase containing a diazepine derivativehaving the following formula (XIa) or a pharmacologically acceptablesalt thereof as an active ingredient:

wherein R¹¹ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, aC₁₋₈ alkoxy group, a C₁₋₈ alkyl group having one to three halogen atoms,a C₁₋₈ alkoxy group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, a C₂₋₈dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈ acylamino grouphaving one to three halogen atoms, a C₁₋₈ alkylsulfonylamino group,carboxyl, a C₂₋₈ acyl group, an alkoxycarbonyl group comprising a C₁₋₈alkoxy moiety, carbamoyl, a C₁₋₈ alkylthio group, a C₁₋₈ alkylsulfinylgroup, a C₁₋₈ alkylsulfonyl group, or sulfamoyl;

each of R¹³ and R¹⁴ independently is hydrogen, a C₁₋₈ alkyl group, aC₁₋₈ alkyl group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, or a C₁₋₃ alkyl group having phenyl;

R¹⁵ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxygroup, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈alkoxy group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, a C₁₋₅alkylamino group having one to five halogen atoms, a C₂₋₈ dialkylaminogroup, a C₂₋₈ acylamino group, a C₂₋₈ acylamino group having one tothree halogen atoms, a C₁₋₈ alkylsulfonylamino group, carboxyl, a C₂₋₈acyl group, an alkoxycarbonyl group comprising a C₁₋₈ alkoxy moiety,carbamoyl, a C₁₋₈ alkylthio group, a C₁₋₈ alkylsulfinyl group, a C₁₋₈alkylsulfonyl group, sulfamoyl, phenyl optionally having one or moresubstituents, or a heterocyclic group optionally having one or moresubstituents;

and

the ring shown below is a heterocyclic ring selected from the groupconsisting of thiophene ring, pyridine ring, pyrimidine ring, quinolinering, indole ring, indoline ring, benzimidazole ring, indazole ring,benzisoxazole ring, and benzotriazole ring, and the ring is combinedwith X at the carbon atom contained in the heterocyclic ring as themember of the ring;

The invention further relates to a compound having the following formula(XII) or a pharmacologically acceptable salt thereof:

wherein each of R¹ and R² independently is hydrogen, a C₁₋₈ alkyl group,a C₂₋₈ alkenyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having oneto three halogen atoms, a C₁₋₈ alkoxy group having one to three halogenatoms, an aralkyl group comprising a C₆₋₁₀ aryl moiety and a C₁₋₃alkylene moiety, a halogen atom, hydroxyl, nitro, cyano, amino, a C₁₋₈alkylamino group, a C₂₋₈ dialkylamino group, a C₂₋₈ acylamino group, aC₂₋₈ acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonylgroup comprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthiogroup, a C₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, orsulfamoyl;

R³ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkylgroup having one to three halogen atoms, or an aralkyl group comprisinga C₆₋₁₀ aryl moiety and a C₁₋₃ alkylene moiety;

R⁴ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxygroup, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈alkoxy group having one to three halogen atoms, an aralkyl groupcomprising a C₆₋₁₀ aryl moiety and a C₁₋₃ alkylene moiety, a C₁₋₈ alkylgroup having hydroxyl, a halogen atom, hydroxyl, nitro, cyano, amino, aC₁₋₈ alkylamino group, a C₁₋₅ alkylamino group having one to fivehalogen atoms, a C₂₋₈ dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, benzenesulfonylamino optionally having one ormore substituents, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonyl groupcomprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthio group, aC₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, sulfamoyl, phenyloptionally having one or more substituents, or a heterocyclic groupoptionally having one or more substituents;

the ring shown below is a five-membered to eight-membered ringoptionally comprising one or more heteroatoms selected from N, S, and Oas the members of the ring, and being condensed with the benzene ring at1- and 2-positions of the benzene ring; and

the ring shown below is an aromatic ring selected from the groupconsisting of benzene ring, naphthalene ring, pyridine ring, pyrimidinering, quinoline ring, indole ring, indoline ring, benzimidazole ring,indazole ring, benzisoxazole ring, and benzotriazole ring.

The invention further relates to a compound having the following formula(XIIa) or a pharmacologically acceptable salt thereof:

wherein each of R¹¹ and R¹² independently is hydrogen, a C₁₋₈ alkylgroup, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl grouphaving one to three halogen atoms, a C₁₋₈ alkoxy group having one tothree halogen atoms, an aralkyl group comprising a C₆₋₁₀ aryl moiety anda C₁₋₃ alkylene moiety, a halogen atom, hydroxyl, nitro, cyano, amino, aC₁₋₈ alkylamino group, a C₂₋₈ dialkylamino group, a C₂₋₈ acylaminogroup, a C₂₋₈ acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonylgroup comprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthiogroup, a C₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, orsulfamoyl;

R¹³ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkylgroup having one to three halogen atoms, or an aralkyl group comprisinga C₆₋₁₀ aryl moiety and a C₁₋₃ alkylene moiety;

R¹⁴ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxygroup, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈alkoxy group having one to three halogen atoms, an aralkyl groupcomprising a C₆₋₁₀ aryl moiety and a C₁₋₃ alkylene moiety, a C₁₋₈ alkylgroup having hydroxyl, a halogen atom, hydroxyl, nitro, cyano, amino, aC₁₋₈ alkylamino group, a C₁₋₅ alkylamino group having one to fivehalogen atoms, a C₂₋₈ dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, benzenesulfonylamino optionally having one ormore substituents, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonyl groupcomprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthio group, aC₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, sulfamoyl, phenyloptionally having one or more substituents, or a heterocyclic groupoptionally having one or more substituents; and

the ring shown below is naphthalene ring, tetrahydronaphthalene ring, orindan ring.

The invention further relates to a compound having the following formula(XIII) or a pharmacologically acceptable salt thereof:

wherein each of R¹ and R² independently is hydrogen, a C₁₋₈ alkyl group,a C₂₋₈ alkenyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having oneto three halogen atoms, a C₁₋₈ alkoxy group having one to three halogenatoms, an aralkyl group comprising a C₆₋₁₀ aryl moiety and a C₁₋₃alkylene moiety, a halogen atom, hydroxyl, nitro, cyano, amino, a C₁₋₈alkylamino group, a C₂₋₈ dialkylamino group, a C₂₋₈ acylamino group, aC₂₋₈ acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonylgroup comprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthiogroup, a C₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, orsulfamoyl;

R³ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkylgroup having one to three halogen atoms, or an aralkyl group comprisinga C₆₋₁₀ aryl moiety and a C₁₋₃ alkylene moiety;

R⁴ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxygroup, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈alkoxy group having one to three halogen atoms, an aralkyl groupcomprising a C₆₋₁₀ aryl moiety and a C₁₋₃ alkylene moiety, a C₁₋₈ alkylgroup having hydroxyl, a halogen atom, hydroxyl, nitro, cyano, amino, aC₁₋₈ alkylamino group, a C₁₋₅ alkylamino group having one to fivehalogen atoms, a C₂₋₈ dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, benzenesulfonylamino optionally having one ormore substituents, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonyl groupcomprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthio group, aC₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, sulfamoyl, phenyloptionally having one or more substituents, or a heterocyclic groupoptionally having one or more substituents;

the ring shown below is a five-membered to eight-membered ringoptionally comprising one or two nitrogen atoms as the members of thering, and being condensed with the benzene ring at 1- and 2-positions ofthe benzene ring; and

the ring shown below is an aromatic ring selected from the groupconsisting of benzene ring, naphthalene ring, pyridine ring, pyrimidinering, quinoline ring, indole ring, indoline ring, benzimidazole ring,pyrazole ring, indazole ring, benzisoxazole ring, and benzotriazolering;

provided that R⁴ is not hydrogen, a C₁₋₈ alkyl group, or a halogen atomin the case that the ring shown below is benzene ring.

The invention further relates to a compound having the following formula(XIIIa) or a pharmacologically acceptable salt thereof:

wherein each of R¹¹ and R¹² independently is hydrogen, a C₁₋₈ alkylgroup, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl grouphaving one to three halogen atoms, a C₁₋₈ alkoxy group having one tothree halogen atoms, an aralkyl group comprising a C₆₋₁₀ aryl moiety anda C₁₋₃ alkylene moiety, a halogen atom, hydroxyl, nitro, cyano, amino, aC₁₋₈ alkylamino group, a C₂₋₈ dialkylamino group, a C₂₋₈ acylaminogroup, a C₂₋₈ acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonylgroup comprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthiogroup, a C₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, orsulfamoyl;

R¹³ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkylgroup having one to three halogen atoms, or an aralkyl group comprisinga C₆₋₁₀ aryl moiety and a C₁₋₃ alkylene moiety;

R¹⁴ is a C₂₋₈ alkenyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl grouphaving one to three halogen atoms, a C₁₋₈ alkoxy group having one tothree halogen atoms, an aralkyl group comprising a C₆₋₁₀ aryl moiety anda C₁₋₃ alkylene moiety, a C₁₋₈ alkyl group having hydroxyl, hydroxyl,nitro, cyano, amino, a C₁₋₈ alkylamino group, a C₁₋₅ alkylamino grouphaving one to five halogen atoms, a C₂₋₈ dialkylamino group, a C₂₋₈acylamino group, a C₂₋₈ acylamino group having one to three halogenatoms, a C₁₋₈ alkylsulfonylamino group, benzenesulfonylamino optionallyhaving one or more substituents, carboxyl, a C₂₋₈ acyl group, analkoxycarbonyl group comprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈alkylthio group, a C₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group,sulfamoyl, phenyl optionally having one or more substituents, or aheterocyclic group optionally having one or more substituents; and

the ring shown below is naphthalene ring, tetrahydronaphthalene ring, orindan ring.

BRIEF DESCRIPTIONS OF THE DRAWINGS

FIG. 1 shows fluorescent double immunohistostaining images within theposterior horn area of spinal L5 after HSV-1 virus infection in Example2.

The cells positive to both the OX42 antibody, which is expressedspecific to the microglia, and the P2X₄ receptor antibody are brightlyshown (the area indicated by the arrow and the area circled with thedotted line).

The right figures show HSV-1 virus inoculation, and the left figuresshow non-virus inoculation.

The upper figures show the whole image of the spinal posterior horn, andthe lower figures show the enlarged image.

FIG. 2 is a graph showing the results of the RT-real time PCR analysisusing Iba1 protein mRNA expression changes caused by herpes zostermanifestation in Example 2.

FIG. 3 is a graph showing the results of RT-real time PCR analysis ofmRNA expression of P2X₄ receptor protein caused by herpes zostermanifestation in Example 2.

FIG. 4 is graphs showing influences of oral administration of paroxetineon acute phase pain of herpes zoster in Example 3.

The right is a graph showing the influences of paroxetine seven daysafter virus inoculation, and the left is a graph showing the influencesof paroxetine thirty days after virus inoculation.

FIG. 5 is a graph showing the effect of the compound A onzoster-associated pain in acute phase in Example 4.

THE EMBODIMENTS OF THE INVENTION

The present invention is described below in more detail.

The active ingredients of the agent of the invention for preventing ortreating zoster-associated pain in acute phase include the followingcompounds.

-   (1) P2X₄ receptor antagonist.-   (2) A compound having the following formula (I) or a    pharmacologically acceptable salt thereof:

wherein R¹ is a halogen atom; and

R² is hydrogen, a halogen atom, nitro, cyano, —C(O)—OR³, —C(O)—NR⁴R⁵,—SO₂—OR³, or —SO₂—NR⁴R⁵, wherein each of R³, R⁴, and R⁵ is hydrogen or aC₁₋₆ alkyl group; or in the alternative

R¹ is hydrogen; and

R² is a halogen atom, nitro, cyano, —C(O)—OR³, —C(O)—NR⁴R⁵, —SO₂—OR³, or—SO₂—NR⁴R⁵, wherein each of R³, R⁴, and R⁵ is hydrogen or a C₁₋₆ alkylgroup.

-   (3) A compound having the formula (I) described in (2) or a    pharmacologically acceptable salt thereof:    wherein R¹ is chloro or bromo; and

R² is hydrogen, chloro, bromo, nitro, cyano, or —C(O)—OR³, or—C(O)—NR⁴R⁵, wherein each of R³, R⁴, and R⁵ is hydrogen or a C₁₋₄ alkylgroup; or in the alternative

R¹ is hydrogen; and

R² is chloro, bromo, nitro, cyano, —C(O)—OR³, or —C(O)—NR⁴R⁵, whereineach of R³, R⁴, and R⁵ is hydrogen or a C₁₋₄ alkyl group.

-   (4) A compound having the following formula (Ia) or a    pharmacologically acceptable salt thereof:

wherein R¹ is chloro or bromo; and

R² is hydrogen, chloro, bromo, nitro, or cyano; or in the alternative

R¹ is hydrogen; and

R² is chloro, bromo, nitro, or cyano.

-   (5) A compound having the following formula (II) or a    pharmacologically acceptable salt thereof:

wherein R is a C₁₋₄ alkyl group, a C₂₋₄ alkynyl group, phenyl optionallyhaving one or more substituents selected from the group consisting of alower alkyl group, an alkylthio group, an alkoxy group, a halogen atom,nitro, an acylamino group, methylsulfonyl, and methylenedioxy, ortetrahydronaphthyl;

R¹ is hydrogen; and

X is hydrogen, a C₁₋₄ alkyl group, a trifluoroalkyl group, hydroxyl, ahalogen atom, methylthio, or an arylalkoxy group.

-   (6) A selective serotonin reuptake inhibitor.-   (7) Imipramine, nortriptyline, amitriptyline, desipramine, doxepin,    fluoxetine, fluvoxamine, citalopram, or a pharmacologically    acceptable salt thereof.-   (8) A compound having the following formula (III) or a    pharmacologically acceptable salt thereof:

wherein X is S or CH₂;

Y is O, S, or NH;

R¹ is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkyl group having one ormore halogen atoms, an aralkyl group comprising a C₁₋₆ alkyl moiety anda C₆₋₁₀ aryl moiety, a C₂₋₈ alkenyl group, carboxymethyl, or analkoxycarbonylmethyl group comprising a C₁₋₈ alkoxy moiety;

each of R² and R³ independently is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈alkoxy group, a C₁₋₈ alkyl group having one or more halogen atoms, aC₁₋₈ alkoxy group having one or more halogen atoms, a halogen atom,amino, carboxyl, hydroxyl, nitro, cyano, a C₂₋₈ acyl group, a C₆₋₁₀ arylgroup, or a five-membered or six-membered heterocyclic group;

each of R⁴ and R⁵ independently is hydrogen, a C₁₋₈ alkyl group, or aC₁₋₈ alkyl group having one or more halogen atoms; and

the double line consisting of a broken line and a solid line is a singlebond or a double bond.

-   (9) A compound having the formula (III) described in (8) or a    pharmacologically acceptable salt thereof, wherein X is S.-   (10) A compound having the formula (III) described in (8) or a    pharmacologically acceptable salt thereof, wherein Y is O.-   (11) A compound having the formula (III) described in (8) or a    pharmacologically acceptable salt thereof, wherein R¹ is hydrogen or    a C₁₋₈ alkyl group.-   (12) A compound having the formula (III) described in (8) or a    pharmacologically acceptable salt thereof, wherein each of R² and R³    independently is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group,    a C₁₋₈ alkyl group having one or more halogen atoms, a C₁₋₈ alkoxy    group having one or more halogen atoms, a halogen atom, amino,    carboxyl, hydroxyl, nitro, or cyano.-   (13) A compound having the formula (III) described in (8) or a    pharmacologically acceptable salt thereof, wherein R³ is hydrogen,    and R² is a halogen atom or hydroxyl.-   (14) A compound having the formula (III) described in (8) or a    pharmacologically acceptable salt thereof, wherein R² substitutes at    meta-position.-   (15) A compound having the formula (III) described in (8) or a    pharmacologically acceptable salt thereof, wherein each of R⁴ and R⁵    is hydrogen.-   (16) A compound having the formula (III) described in (8) or a    pharmacologically acceptable salt thereof, wherein the double line    consisting of a broken line and a solid line is a double bond.-   (17) A compound having the following formula (IV) or a    pharmacologically acceptable salt thereof:

wherein X^(a) is O, S, or NH;

R^(1a) is hydroxyl, tetrazolyl, N(R^(5a))(R^(6a)), a C₂₋₈ alkenyl group,a C₂₋₈ alkynyl group, a C₁₋₈ alkyl group having one or more halogenatoms, a C₁₋₈ alkoxy group having one or more halogen atoms, or a C₆₋₁₀aryl group, wherein R^(5a) is hydrogen or a C₁₋₈ alkyl group, and R^(6a)is hydrogen, a C₁₋₈ alkyl group, or a C₂₋₈ acyl group;

each of R^(2a) and R^(3a) independently is hydrogen, a C₁₋₈ alkyl group,or a C₁₋₈ alkyl group having one or more halogen atoms; and

R^(4a) is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈alkyl group having one or more halogen atoms, a halogen atom, hydroxyl,nitro, amino, carboxyl, tetrazolyl, cyano, a C₆₋₁₀ aryl group, or afive-membered or six-membered heterocyclic group.

-   (18) A compound having the formula (IV) described in (17) or a    pharmacologically acceptable salt thereof, wherein X^(a) is O.-   (19) A compound having the formula (IV) described in (17) or a    pharmacologically acceptable salt thereof, wherein R^(1a) is    hydroxyl, amino, a C₁₋₈ alkylamino group, a C₂₋₁₂ dialkylamino    group, a C₁₋₈ alkyl group having one or more halogen atoms, or    phenyl.-   (20) A compound having the formula (IV) described in (17) or a    pharmacologically acceptable salt thereof, wherein R^(1a)    substitutes at meta-position.-   (21) A compound having the formula (IV) described in (17) or a    pharmacologically acceptable salt thereof, wherein each of R^(2a)    and R^(3a) is hydrogen.-   (22) A compound having the formula (IV) described in (17) or a    pharmacologically acceptable salt thereof, wherein R^(4a) is    hydrogen.-   (23) A compound having the following formula (IVa) or a    pharmacologically acceptable salt thereof:

wherein X^(b) is O, S, or NH;

R^(1b) is a halogen atom, hydroxyl, tetrazolyl, N(R^(5b))(R^(6b)), aC₂₋₈ alkenyl group, a C₂₋₈ alkynyl group, a C₁₋₈ alkyl group having oneor more halogen atoms, a C₁₋₈ alkoxy group having one or more halogenatoms, or a C₆₋₁₀ aryl group, wherein R^(5b) is hydrogen or a C₁₋₈ alkylgroup, and R^(6b) is hydrogen, a C₁₋₈ alkyl group, or a C₂₋₈ acyl group;

each of R^(2b) and R^(3b) independently is hydrogen, a C₁₋₈ alkyl group,or a C₁₋₈ alkyl group having one or more halogen atoms;

R^(4b) is hydrogen, a C₁₋₈ alkyl group, an alkoxy group, a C₁₋₈ alkylgroup having one or more halogen atoms, a halogen atom, hydroxyl, nitro,amino, carboxyl, tetrazolyl, cyano, a C₆₋₁₀ aryl group, or afive-membered or six-membered heterocyclic group; and

R^(7b) is a C₁₋₈ alkyl group.

-   (24) A compound having the formula (IVa) described in (23) or a    pharmacologically acceptable salt thereof, wherein X^(b) is O.-   (25) A compound having the formula (IVa) described in (23) or a    pharmacologically acceptable salt thereof, wherein R^(1b) is a    halogen atom, hydroxyl, amino, a C₁₋₈ alkylamino group, dialkylamino    group, a C₁₋₈ alkyl group having one or more halogen atoms, or    phenyl.-   (26) A compound having the formula (IVa) described in (23) or a    pharmacologically acceptable salt thereof, wherein R^(1b)    substitutes at meta-position.-   (27) A compound having the formula (IVa) described in (23) or a    pharmacologically acceptable salt thereof, wherein each of R^(2b)    and R^(3b) is hydrogen.-   (28) A compound having the formula (IVa) described in (23) or a    pharmacologically acceptable salt thereof, wherein R^(4b) is    hydrogen.-   (29) A compound having the following formula (IVb) or a    pharmacologically acceptable salt thereof:

wherein X^(c) is O, S, or NH;

R^(1c) is hydrogen, a halogen atom, a C₁₋₈ alkyl group, a C₁₋₈ alkoxygroup, hydroxyl, tetrazolyl, N(R^(5c))(R^(6c)), a C₂₋₈ alkenyl group, aC₂₋₈ alkynyl group, a C₁₋₈ alkyl group having one or more halogen atoms,a C₁₋₈ alkoxy group having one or more halogen atoms, or a C₆₋₁₀ arylgroup, wherein R^(5c) is hydrogen or a C₁₋₈ alkyl group, and R^(6c) ishydrogen, a C₁₋₈ alkyl group, or a C₂₋₈ acyl group;

each of R^(2c) and R^(3c) independently is hydrogen, a C₁₋₈ alkyl group,or a C₁₋₈ alkyl group having one or more halogen atoms;

R^(4c) is hydrogen, a C₁₋₈ alkyl group, an alkoxy group, a C₁₋₈ alkylgroup having one or more halogen atoms, a halogen atom, hydroxyl, nitro,amino, carboxyl, tetrazolyl, cyano, a C₆₋₁₀ aryl group, or afive-membered or six-membered heterocyclic group;

R^(7c) is hydrogen or a C₁₋₈ alkyl group; and

R^(8c) is hydrogen, a C₁₋₈ alkyl group, or a C₂₋₈ acyl group.

-   (30) A compound having the formula (IVb) described in (29) or a    pharmacologically acceptable salt thereof, wherein X^(c) is O.-   (31) A compound having the formula (IVb) described in (29) or a    pharmacologically acceptable salt thereof, wherein R^(1c) is    hydrogen, a halogen atom, hydroxyl, amino, a C₁₋₈ alkylamino group,    dialkylamino group, a C₁₋₈ alkyl group having one or more halogen    atoms, or phenyl.-   (32) A compound having the formula (IVb) described in (29) or a    pharmacologically acceptable salt thereof, wherein R^(1c)    substitutes at meta-position.-   (33) A compound having the formula (IVb) described in (29) or a    pharmacologically acceptable salt thereof, wherein each of R^(2c)    and R^(3c) is hydrogen.-   (34) A compound having the formula (IVb) described in (29) or a    pharmacologically acceptable salt thereof, wherein R^(4c) is    hydrogen or a halogen atom.-   (35) A compound having the formula (IVb) described in (29) or a    pharmacologically acceptable salt thereof, wherein R^(7c) is    hydrogen.-   (36) A compound having the formula (IVb) described in (29) or a    pharmacologically acceptable salt thereof, wherein R^(8c) is    hydrogen.-   (37) A compound having the following formula (V) or a    pharmacologically acceptable salt thereof:

wherein X is O, S, or NH;

Y is N or NR⁶, wherein R⁶ is hydrogen or a C₁₋₈ alkyl group;

R¹ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkylgroup having one to three halogen atoms, or an alkyl group havingphenyl;

R² is a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group havingone to three halogen atoms, hydroxyl, nitro, amino, carboxyl,tetrazolyl, or cyano;

R³ is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkylgroup having one to three halogen atoms, a halogen atom, hydroxyl,nitro, amino, carboxyl, tetrazolyl, or cyano;

each of R⁴ and R⁵ independently is hydrogen, a C₁₋₈ alkyl group, or aC₁₋₈ alkyl group having one to three halogen atoms;

m is 1 or 2;

when Y is N, the double line consisting of a solid line and a brokenline is a double bond; and

when Y is NR⁶, the double line consisting of a solid line and a brokenline is a single bond.

-   (38) A compound having the formula (V) described in (37) or a    pharmacologically acceptable salt thereof, wherein m is 1.-   (39) A compound having the formula (V) described in (37) or a    pharmacologically acceptable salt thereof, wherein X is O.-   (40) A compound having the formula (V) described in (37) or a    pharmacologically acceptable salt thereof, wherein Y is N.-   (41) A compound having the formula (V) described in (37) or a    pharmacologically acceptable salt thereof, wherein R¹ is hydrogen or    a C₁₋₈ alkyl group.-   (42) A compound having the formula (V) described in (37) or a    pharmacologically acceptable salt thereof, wherein R¹ is hydrogen.-   (43) A compound having the formula (V) described in (37) or a    pharmacologically acceptable salt thereof, wherein each of R⁴ and R⁵    is hydrogen.-   (44) A compound having the formula (V) described in (37) or a    pharmacologically acceptable salt thereof, wherein R² is a C₁₋₈    alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having one to    three halogen atoms, or hydroxyl.-   (45) A compound having the formula (V) described in (37) or a    pharmacologically acceptable salt thereof, wherein R² is a C₁₋₈    alkoxy group or hydroxyl.-   (46) A compound having the formula (V) described in (37) or a    pharmacologically acceptable salt thereof, wherein R³ is hydrogen or    a halogen atom.-   (47) A compound having the formula (V) described in (37) or a    pharmacologically acceptable salt thereof, wherein R³ is hydrogen.-   (48) A compound having the following formula (Va) or a    pharmacologically acceptable salt thereof:

wherein R¹¹ is hydrogen or a C₁₋₈ alkyl group;

R²¹ is a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl grouphaving one to three halogen atoms, or hydroxyyl; and

R³¹ is hydrogen or a halogen atom.

-   (49) A compound having the formula (Va) described in (48) or a    pharmacologically acceptable salt thereof, wherein R¹¹ is hydrogen.-   (50) A compound having the formula (Va) described in (48) or a    pharmacologically acceptable salt thereof, wherein R²¹ is a C₁₋₈    alkoxy group or hydroxyl.-   (51) A compound having the formula (Va) described in (48) or a    pharmacologically acceptable salt thereof, wherein R³¹ is hydrogen.-   (52)    5-(3-methoxyphenyl)-1,3-dihydro-2H-naphtho[1,2-e]-1,4-diazepin-2-one,-   5-(3-hydroxyphenyl)-1,3-dihydro-2H-naphtho[1,2-e]-1,4-diazepin-2-one,-   5-(4-methoxyphenyl)-1,3-dihydro-2H-naphtho[1,2-e]-1,4-diazepin-2-one,-   5-(4-hydroxyphenyl)-1,3-dihydro-2H-naphtho[1,2-e]-1,4-diazepin-2-one,-   5-(4-methylphenyl)-1,3-dihydro-2H-naphtho[1,2-e]-1,4-diazepin-2-one,-   5-(2-methoxyphenyl)-1,3-dihydro-2H-naphtho[1,2-e]-1,4-diazepin-2-one,-   5-(2-hydroxyphenyl)-1,3-dihydro-2H-naphtho[1,2-e]-1,4-diazepin-2-one,-   5-(3,4-dimethoxyphenyl)-1,3-dihydro-2H-naphtho[1,2-e]-1,4-diazepin-2-one,-   5-(3,4-dihydroxyphenyl)-1,3-dihydro-2H-naphtho[1,2-e]-1,4-diazepin-2-one,    or a pharmacologically acceptable salt thereof.-   (53) A compound having the following formula (VI) or a    pharmacologically acceptable salt thereof:

wherein A is an aryl group optionally having one or more substituents ora heterocyclic group optionally having one or more substituents;

B is an aryl group optionally having one or more substituents or aheterocyclic group optionally having one or more substituents;

X is a C₁₋₅ alkylene group or a bond;

Y is a C₁₋₅ alkylene optionally comprising a double bond;

Z is O, S, N(R⁵), or a bond, wherein R⁵ is hydrogen or a C₁₋₈ alkylgroup;

each of R¹, R², and R³ independently is hydrogen, a C₁₋₈ alkyl group, ora C₁₋₈ alkyl group having one to three halogen atoms;

R⁴ is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkyl group having one tothree halogen atoms, a three-membered to seven-membered cycloalkylgroup, or a C₁₋₈ alkyl group having a three-membered to seven-memberedcycloalkyl group; and

each of n and m independently is 1 or 2;

provided that when X is a bond, the substituent of the aryl grouprepresented by A is not an alkyl group.

-   (54) A compound having the formula (VI) described in (53) or a    pharmacologically acceptable salt thereof, wherein A is phenyl or    thienyl, each of which optionally has one to three substituents    selected from the group consisting of a halogen atom, a C₁₋₈ alkyl    group (except that X is a bond), a C₁₋₈ alkyl group having one to    three halogen atoms, nitro, cyano, hydroxyl, amino, a C₁₋₈    alkylamino group, a C₂₋₁₆ dialkylamino group, a C₂₋₈ acylamino    group, a C₁₋₈ alkoxy group, a C₁₋₈ alkoxy group having one to three    halogen atoms, an aryl group, and a heterocyclic group.-   (55) A compound having the formula (VI) described in (53) or a    pharmacologically acceptable salt thereof, wherein A is phenyl    optionally having one to three substituents selected from the group    consisting of selected from the group consisting of a halogen atom,    a C₁₋₈ alkyl group (except that X is a bond), a C₁₋₈ alkoxy group,    and a C₁₋₈ alkyl group having one to three halogen atoms.-   (56) A compound having the formula (VI) described in (53) or a    pharmacologically acceptable salt thereof, wherein B is phenyl,    naphthyl, benzofuranyl, 1,3-benzo[d]dioxolyl, quinolyl, indolyl,    benzothienyl, thienyl, or pyridyl, each of which optionally has one    to three substituents selected from the group consisting of a    halogen atom, a C₁₋₈ alkyl group, a C₁₋₈ alkyl group having one to    three halogen atoms, nitro, cyano, hydroxyl, amino, a C₁₋₈    alkylamino group, a C₂₋₁₆ dialkylamino group, a C₂₋₈ acylamino    group, a C₁₋₈ alkoxy group, a C₁₋₈ alkoxy group having one to three    halogen atoms, a C₆₋₁₂ aryloxy group, a C₂₋₉ alkoxycarbonyl group,    carbamoyl, a C₂₋₉ alkylcarbamoyl group, sulfamoyl, a C₁₋₈    alkylsulfamoyl group, and a C₂₋₁₆ dialkylsulfamoyl group.-   (57) A compound having the formula (VI) described in (53) or a    pharmacologically acceptable salt thereof, wherein B is phenyl,    naphthyl, benzofuranyl, or 1,3-benzo[d]dioxolyl, each of which    optionally has one to three substituents selected from the group    consisting of a halogen atom, a C₁₋₈ alkyl group, a C₁₋₈ alkyl group    having one to three halogen atoms, a C₁₋₈ alkoxy group, a C₆₋₁₂    aryloxy group, sulfamoyl, a C₁₋₈ alkylsulfamoyl group, and a C₂₋₁₆    dialkylsulfamoyl group.-   (58) A compound having the formula (VI) described in (53) or a    pharmacologically acceptable salt thereof, wherein X is a bond.-   (59) A compound having the formula (VI) described in (53) or a    pharmacologically acceptable salt thereof, wherein Y is methylene.-   (60) A compound having the formula (VI) described in (53) or a    pharmacologically acceptable salt thereof, wherein Z is O or S.-   (61) A compound having the formula (VI) described in (53) or a    pharmacologically acceptable salt thereof, wherein each of R¹, R²,    and R³ is hydrogen.-   (62) A compound having the formula (VI) described in (53) or a    pharmacologically acceptable salt thereof, wherein R⁴ is hydrogen or    a C₁₋₈ alkyl group.-   (63) A compound having the formula (VI) described in (53) or a    pharmacologically acceptable salt thereof, wherein R⁴ is hydrogen.-   (64) A compound having the formula (VI) described in (53) or a    pharmacologically acceptable salt thereof, wherein each of n and m    is 1.-   (65) A compound having the following formula (VIa) or a    pharmacologically acceptable salt thereof:

wherein A¹ is phenyl or thienyl, each of which optionally has one tothree substituents selected from the group consisting of a halogen atom,a C₁₋₈ alkyl group having one to three halogen atoms, nitro, cyano,hydroxyl, amino, a C₁₋₈ alkylamino group, a C₂₋₁₆ dialkylamino group, aC₂₋₈ acylamino group, a C₁₋₈ alkoxy group, a C₁₋₈ alkoxy group havingone to three halogen atoms, an aryl group, and a heterocyclic group;

B¹ is an aryl group optionally having one or more substituents or aheterocyclic group optionally having one or more substituents;

Y¹ is a C₁₋₅ alkylene chain optionally comprising a double bond;

Z¹ is O, S, N(R⁷), or a bond, wherein R⁷ is hydrogen or a C₁₋₈ alkylgroup; and

R⁶ is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkyl group having one tothree halogen atoms, or a three-membered to seven-membered cycloalkylgroup.

-   (66) A compound having the formula (VIa) described in (65) or a    pharmacologically acceptable salt thereof, wherein A¹ is phenyl    optionally having one to three substituents selected from the group    consisting of a halogen atom, a C₁₋₈ alkyl group having one to three    halogen atoms, and a C₁₋₈ alkoxy group.-   (67) A compound having the formula (VIa) described in (65) or a    pharmacologically acceptable salt thereof, wherein B¹ is phenyl,    naphthyl, benzofuranyl, 1,3-benzo[d]dioxolyl, quinolyl, indolyl,    benzothienyl, thienyl, or pyridyl, each of which optionally has one    to three substituents selected from the group consisting of a    halogen atom, a C₁₋₈ alkyl group, a C₁₋₈ alkyl group having one to    three halogen atoms, nitro, cyano, hydroxyl, amino, a C₁₋₈    alkylamino group, a C₂₋₁₆ dialkylamino group, a C₂₋₈ acylamino    group, a C₁₋₈ alkoxy group, a C₁₋₈ alkoxy group having one to three    halogen atoms, a C₆₋₁₂ aryloxy group, a C₂₋₉ alkoxycarbonyl group,    carbamoyl, a C₂₋₉ alkylcarbamoyl group, sulfamoyl, a C₁₋₈    alkylsulfamoyl group and a C₂₋₁₆ dialkylsulfamoyl group.-   (68) A compound having the formula (VIa) described in (65) or a    pharmacologically acceptable salt thereof, wherein B¹ is phenyl,    naphthyl, benzofuranyl, or 1,3-benzo[d]dioxolyl.-   (69) A compound having the formula (VIa) described in (65) or a    pharmacologically acceptable salt thereof, wherein Y¹ is methylene.-   (70) A compound having the formula (VIa) described in (65) or a    pharmacologically acceptable salt thereof, wherein Z¹ is O or S.-   (71) A compound having the formula (VIa) described in (65) or a    pharmacologically acceptable salt thereof, wherein R⁶ is hydrogen or    a C₁₋₈ alkyl group.-   (72) A compound having the formula (VIa) described in (65) or a    pharmacologically acceptable salt thereof, wherein R⁶ is hydrogen.-   (73) A compound having the following formula (VIb) or a    pharmacologically acceptable salt thereof:

wherein A² is phenyl or thienyl, each of which optionally has one tothree substituents selected from the group consisting of a halogen atom,a C₁₋₈ alkyl group having one to three halogen atoms, nitro, cyano,acetylamino, a C₁₋₈ alkoxy group, a C₁₋₈ alkoxy group having one tothree halogen atoms, an aryl group, and a heterocyclic group;

B² is phenyl, naphthyl, benzofuranyl, 1,3-benzo[d]dioxolyl, quinolyl,indolyl, benzothienyl, thienyl, or pyridyl, each of which optionally hasone to three substituents selected from the group consisting of ahalogen atom, a C₁₋₈ alkyl group, a C₁₋₈ alkyl group having one to threehalogen atoms, nitro, cyano, hydroxyl, amino, a C₂₋₈ acylamino group, aC₁₋₈ alkoxy group, a C₁₋₈ alkoxy group having one to three halogenatoms, a C₆₋₁₂ aryloxy group, sulfamoyl, a C₁₋₈ alkylsulfamoyl group,and a C₂₋₁₆ dialkylsulfamoyl group;

Z² is O, S, or NH; and

R⁸ is hydrogen or a C₁₋₈ alkyl group.

-   (74) A compound having the formula (VIb) described in (73) or a    pharmacologically acceptable salt thereof, wherein A² is phenyl    optionally having one to three substituents selected from the group    consisting of a halogen atom, a C₁₋₈ alkyl group having one to three    halogen atoms, a C₁₋₈ alkoxy group, nitro, cyano, or acetylamino.-   (75) A compound having the formula (VIb) described in (73) or a    pharmacologically acceptable salt thereof, wherein A² is phenyl    optionally having one to three substituents selected from the group    consisting of a halogen atom, a C₁₋₈ alkyl group having one to three    halogen atoms, and a C₁₋₈ alkoxy group.-   (76) A compound having the formula (VIb) described in (73) or a    pharmacologically acceptable salt thereof, wherein B² is phenyl,    naphthyl, benzofuranyl, or 1,3-benzo[d]dioxolyl, each of which    optionally has one to three substituents selected from the group    consisting of a halogen atom, a C₁₋₈ alkyl group, or a C₁₋₈ alkyl    group having one to three halogen atoms, an aryloxy group,    sulfamoyl, a C₁₋₈ alkylsulfamoyl group, and a C₂₋₁₆ dialkylsulfamoyl    group.-   (77) A compound having the formula (VIb) described in (73) or a    pharmacologically acceptable salt thereof, wherein Z² is O or S.-   (78) A compound having the formula (VIb) described in (73) or a    pharmacologically acceptable salt thereof, wherein R⁸ is hydrogen.-   (79) 1-(4-fluorophenyl)-2-(4-phenoxyphenoxymethyl)piperazine,-   1-(4-fluorophenyl)-2-(4-phenoxyphenylsulfanylmethyl)piperazine,-   2-(4-chlorophenoxymethyl)-1-(4-isopropoxyphenyl) piperazine,-   2-(2,4-dichlorophenoxymethyl)-1-(4-isopropoxyphenyl)piperazine,-   2-(4-tert-butoxyphenoxymethyl)-1-(4-isopropoxyphenyl) piperazine,-   2-(4-chlorophenoxymethyl)-1-(3-methoxyphenyl)piperazine,-   2-(4-chlorophenoxymethyl)-1-(2-methoxyphenyl) piperazine, or

a pharmacologically acceptable salt thereof.

-   (80) A compound having the following formula (VII) or a    pharmacologically acceptable salt thereof:

wherein B is an aryl group optionally having one or more substituents ora heterocyclic group optionally having one or more substituents;

Y is a C₁₋₅ alkylene optionally comprising a double bond;

Z is O, S, N(R⁵), or a bond, wherein R⁵ is hydrogen or a C₁₋₈ alkylgroup;

each of R¹, R², and R³ independently is hydrogen, a C₁₋₈ alkyl group, ora C₁₋₈ alkyl group having one to three halogen atoms;

R⁴ is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkyl group having one tothree halogen atoms, a three-membered to seven-membered cycloalkylgroup, or a C₁₋₈ alkyl group having a three-membered to seven-memberedcycloalkyl group;

each of P and Q independently is hydrogen, a halogen atom, a C₁₋₈ alkylgroup, a C₁₋₈ alkyl group having one to three halogen atoms, nitro,cyano, hydroxyl, amino, a C₁₋₈ alkylamino group, a C₂₋₁₆ dialkylaminogroup, a C₂₋₈ acylamino group, a C₁₋₈ alkoxy group, a C₁₋₈ alkoxy grouphaving one to three halogen atoms, or a heterocyclic group;

W is a C₁₋₈ alkyl group or a three-membered to seven-membered cycloalkylgroup; or

when P and W are placed at 2- and 3-positions or 3- and 4-positions ofphenyl, P and W are combined to form propylene or tetramethylene; and

each of n and m independently is 1 or 2.

-   (81) A compound having the formula (VII) described in (80) or a    pharmacologically acceptable salt thereof, wherein B is phenyl,    naphthyl, benzofuranyl, indolyl, benzothienyl, or thienyl optionally    having one to three substituents selected from the group consisting    of a halogen atom, a C₁₋₈ alkyl group, a C₁₋₈ alkyl group having one    to three halogen atoms, nitro, cyano, hydroxyl, amino, a C₁₋₈    alkylamino group, a C₂₋₁₆ dialkylamino group, a C₂₋₈ acylamino    group, a C₁₋₈ alkoxy group, a C₁₋₈ alkoxy group having one to three    halogen atoms, a C₆₋₁₂ aryloxy group, an arylalkoxy group comprising    a C₁₋₈ alkyl moiety, a C₂₋₉ alkoxycarbonyl group, carbamoyl, a C₂₋₉    alkylcarbamoyl group, sulfamoyl, a C₁₋₈ alkylsulfamoyl group, and a    C₂₋₁₆ dialkylsulfamoyl group.-   (82) A compound having the formula (VII) described in (80) or a    pharmacologically acceptable salt thereof, wherein B is phenyl    optionally having one to three substituents selected from the group    consisting of selected from the group consisting of a halogen atom,    a C₁₋₈ alkyl group, a C₁₋₈ alkyl group having one to three halogen    atoms, nitro, cyano, hydroxyl, amino, a C₁₋₈ alkylamino group, a    C₂₋₁₆ dialkylamino group, a C₂₋₈ acylamino group, a C₁₋₈ alkoxy    group, a C₁₋₈ alkoxy group having one to three halogen atoms, a    C₆₋₁₂ aryloxy group, an arylalkoxy group comprising a C₁₋₈ alkyl    moiety, a C₂₋₉ alkoxycarbonyl group, carbamoyl, a C₂₋₉    alkylcarbamoyl group, sulfamoyl, a C₁₋₈ alkylsulfamoyl group, and a    C₂₋₁₆ dialkylsulfamoyl group.-   (83) A compound having the formula (VII) described in (80) or a    pharmacologically acceptable salt thereof, wherein each of P and Q    independently is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkyl group    having one to three halogen atoms, or a C₁₋₈ alkoxy group.-   (84) A compound having the formula (VII) described in (80) or a    pharmacologically acceptable salt thereof, wherein each of P and Q    is hydrogen.-   (85) A compound having the formula (VII) described in (80) or a    pharmacologically acceptable salt thereof, wherein W is a C₃₋₆ alkyl    group.-   (86) A compound having the formula (VII) described in (80) or a    pharmacologically acceptable salt thereof, wherein W is n-propyl,    isopropyl, n-butyl, or isobutyl.-   (87) A compound having the formula (VII) described in (80) or a    pharmacologically acceptable salt thereof, wherein each of n and m    is 1.-   (88) A compound having the formula (VII) described in (80) or a    pharmacologically acceptable salt thereof, wherein Y is methylene.-   (89) A compound having the formula (VII) described in (80) or a    pharmacologically acceptable salt thereof, wherein Z is O or S.-   (90) A compound having the formula (VII) described in (80) or a    pharmacologically acceptable salt thereof, wherein each of R¹, R²,    and R³ is hydrogen.-   (91) A compound having the formula (VII) described in (80) or a    pharmacologically acceptable salt thereof, wherein R⁴ is hydrogen or    a C₁₋₈ alkyl group.-   (92) A compound having the formula (VII) described in (80) or a    pharmacologically acceptable salt thereof, wherein R⁴ is hydrogen.-   (93) A compound having the formula (VII) described in (80) or a    pharmacologically acceptable salt thereof: wherein R⁴ is hydrogen;

Y is methylene;

Z is O or S; and

B is phenyl optionally having one to three substituents selected fromthe group consisting of a halogen atom, a C₁₋₈ alkyl group, a C₁₋₈ alkylgroup having one to three halogen atoms, cyano, hydroxyl, a C₁₋₈ alkoxygroup, a C₁₋₈ alkoxy group having one to three halogen atoms, benzyloxy,sulfamoyl, and a C₁₋₈ alkylsulfamoyl group.

-   (94) 2-(4-chlorophenoxymethyl)-1-(4-isopropylphenyl) piperazine,-   2-(4-chlorophenoxymethyl)-1-(4-propylphenyl) piperazine,-   2-(4-chlorophenoxymethyl)-1-(3-isopropylphenyl) piperazine,-   2-(4-chlorophenoxymethyl)-1-(2,4,6-trimethylphenyl)piperazine,-   2-(4-chlorophenoxymethyl)-1-indan-5-yl-piperazine,-   1-(4-isopropylphenyl)-2-[4-(isopropylsulfamoyl)phenoxymethyl]piperazine,-   2-(4-chlorophenylsulfanylmethyl)-1-(4-isopropylphenyl)piperazine,-   1-(3-isopropylphenyl)-2-[4-(isopropylsulfamoyl)phenoxymethyl]piperazine,-   1-(4-isopropylphenyl)-2-(4-phenoxyphenoxymethyl)piperazine, or

a pharmacologically acceptable salt thereof.

-   (95) A compound having the following formula (VIII) or a    pharmacologically acceptable salt thereof:

wherein R¹ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈alkyl group having one to three halogen atoms, or a C₁₋₃ alkyl grouphaving phenyl;

R² is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkylgroup having one to three halogen atoms, a C₁₋₈ alkoxy group having oneto three halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino, aC₁₋₈ alkylamino group, a C₂₋₈ dialkylamino group, a C₂₋₈ acylaminogroup, a C₂₋₈ acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonylgroup comprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthiogroup, a C₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, orsulfamoyl;

R³ is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkylgroup having one to three halogen atoms, a C₁₋₈ alkoxy group having oneto three halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino,carboxyl, a C₂₋₈ acyl group, or an alkoxycarbonyl group comprising aC₁₋₈ alkoxy moiety; and

each of R⁴ and R⁵ independently is hydrogen, a C₁₋₈ alkyl group, or aC₁₋₈ alkyl group having one to three halogen atoms.

-   (96) A compound having the formula (VIII) described in (95) or a    pharmacologically acceptable salt thereof, wherein R¹ is hydrogen or    a C₁₋₈ alkyl group.-   (97) A compound having the formula (VIII) described in (95) or a    pharmacologically acceptable salt thereof, wherein R¹ is hydrogen.-   (98) A compound having the formula (VIII) described in (95) or a    pharmacologically acceptable salt thereof, wherein R⁴ is hydrogen,    and R⁵ is hydrogen or a C₁₋₈ alkyl group.-   (99) A compound having the formula (VIII) described in (95) or a    pharmacologically acceptable salt thereof, wherein each of R⁴ and R⁵    is hydrogen.-   (100) A compound having the formula (VIII) described in (95) or a    pharmacologically acceptable salt thereof, wherein R² is a C₁₋₈    alkoxy group, hydroxyl, carboxyl, cyano, or an alkoxycarbonyl group    comprising a C₁₋₈ alkoxy moiety.-   (101) A compound having the formula (VIII) described in (95) or a    pharmacologically acceptable salt thereof, wherein R² is a C₁₋₈    alkoxy group or hydroxyl.-   (102) A compound having the formula (VIII) described in (95) or a    pharmacologically acceptable salt thereof, wherein R³ is hydrogen.-   (103) A compound having the following formula (IX) or a    pharmacologically acceptable salt thereof:

wherein R¹ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈alkyl group having one to three halogen atoms, or a C₁₋₃ alkyl grouphaving phenyl;

each of R² and R³ independently is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈alkoxy group, a C₁₋₈ alkyl group having one to three halogen atoms, aC₁₋₈ alkoxy group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, a C₂₋₈dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈ acylamino grouphaving one to three halogen atoms, a C₁₋₈ alkylsulfonylamino group,carboxyl, a C₂₋₈ acyl group, an alkoxycarbonyl group comprising a C₁₋₈alkoxy moiety, carbamoyl, a C₁₋₈ alkylthio group, a C₁₋₈ alkylsulfinylgroup, a C₁₋₈ alkylsulfonyl group, or sulfamoyl;

each of R⁴ and R⁵ independently is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈alkyl group having one to three halogen atoms, or a C₁₋₃ alkyl grouphaving phenyl; and

W is a five-membered or six-membered heterocyclic ring optionally havingone or more substituents and comprising one to four nitrogen atoms asthe members of the ring.

-   (104) A compound having the formula (IX) described in (103) or a    pharmacologically acceptable salt thereof, wherein W is tetrazole,    1,2,4-triazole, 1,2,3-triazole, 1,2,4-oxadiazole, pyrazole, or    imidazole, each of which optionally has one or more substituents    selected from the group consisting of a C₁₋₈ alkyl group, a C₁₋₈    alkyl group having one to three halogen atoms, a halogen atom,    cyano, oxo, and thioxo.-   (105) A compound having the formula (IX) described in (103) or a    pharmacologically acceptable salt thereof, wherein W is tetrazole,    1,2,4-triazole, or 1,2,3-triazole, each of which optionally has one    or more substituents selected from the group consisting of a C₁₋₈    alkyl group, a C₁₋₈ alkyl group having one to three halogen atoms, a    halogen atom, and cyano.-   (106) A compound having the formula (IX) described in (103) or a    pharmacologically acceptable salt thereof, wherein W is    5-oxo-1,2,4-oxadiazole or 5-thioxo-1,2,4-oxadiazole.-   (107) A compound having the formula (IX) described in (103) or a    pharmacologically acceptable salt thereof, wherein W is tetrazole.-   (108) A compound having the formula (IX) described in (103) or a    pharmacologically acceptable salt thereof, wherein R¹ is hydrogen or    a C₁₋₈ alkyl group.-   (109) A compound having the formula (IX) described in (103) or a    pharmacologically acceptable salt thereof, wherein R¹ is hydrogen.-   (110) A compound having the formula (IX) described in (103) or a    pharmacologically acceptable salt thereof, wherein R⁴ is hydrogen,    and R⁵ is hydrogen or a C₁₋₈ alkyl group.-   (111) A compound having the formula (IX) described in (103) or a    pharmacologically acceptable salt thereof, wherein each of R⁴ and R⁵    is hydrogen.-   (112) A compound having the formula (IX) described in (103) or a    pharmacologically acceptable salt thereof, wherein R² is hydrogen, a    C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having one    to three halogen atoms, a C₁₋₈ alkoxy group having one to three    halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino,    carboxyl, a C₂₋₈ acyl group, or an alkoxycarbonyl group comprising a    C₁₋₈ alkoxy moiety.-   (113) A compound having the formula (IX) described in (103) or a    pharmacologically acceptable salt thereof, wherein R² is hydrogen.-   (114) A compound having the formula (IX) described in (103) or a    pharmacologically acceptable salt thereof, wherein R³ is hydrogen, a    C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having one    to three halogen atoms, a C₁₋₈ alkoxy group having one to three    halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino,    carboxyl, a C₂₋₈ acyl group, or an alkoxycarbonyl group comprising a    C₁₋₈ alkoxy moiety.-   (115) A compound having the formula (IX) described in (103) or a    pharmacologically acceptable salt thereof, wherein R³ is hydrogen.-   (116)    5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione    sodium salt.-   (117) Paroxetine or a pharmacologically acceptable salt thereof.-   (118) A diazepine derivative having the following formula (X) or a    pharmacologically acceptable salt thereof:

wherein each of R¹ and R² independently is hydrogen, a C₁₋8 alkyl group,a C₂₋₈ alkenyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having oneto three halogen atoms, a C₁₋₈ alkoxy group having one to three halogenatoms, a halogen atom, hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylaminogroup, a C₂₋₈ dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonylgroup comprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthiogroup, a C₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, orsulfamoyl;

R³ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkylgroup having one to three halogen atoms, or a C₁₋₃ alkyl group havingphenyl;

each of R⁴ and R⁵ independently is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈alkyl group having one to three halogen atoms, a halogen atom, hydroxyl,nitro, cyano, amino, or a C₁₋₃ alkyl group having phenyl;

R⁶ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxygroup, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈alkoxy group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, a C₂₋₈dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈ acylamino grouphaving one to three halogen atoms, a C₁₋₈ alkylsulfonylamino group,carboxyl, a C₂₋₈ acyl group, an alkoxycarbonyl group comprising a C₁₋₈alkoxy moiety, carbamoyl, a C₁₋₈ alkylthio group, a C₁₋₈ alkylsulfinylgroup, a C₁₋₈ alkylsulfonyl group, sulfamoyl, phenyl optionally havingone or more substituents, or a heterocyclic group optionally having oneor more substituents;

the ring shown below is a five-membered to eight-membered non-aromaticring optionally comprising one or two heteroatoms selected from N, S,and O, and being condensed with the benzene ring at 1- and 2-positionsof the benzene ring;

the ring shown below is an aromatic ring selected from the groupconsisting of benzene ring, naphthalene ring, thiophene ring, pyridinering, pyrimidine ring, indole ring, indazole ring, benzotriazole ring,benzisoxazole ring, benzimidazole ring, and quinoline ring;

Z is O or S;

when X is N, Y is C═O or C═S, and the double line consisting of a solidline and a broken line is a single bond; and

when X is C, Y is N, and the double line consisting of a solid line anda broken line is a double bond.

-   (119) A diazepine derivative having the following formula (Xa) or a    pharmacologically acceptable salt thereof:

wherein each of R¹¹ and R¹² independently is hydrogen, a C₁₋₈ alkylgroup, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl grouphaving one to three halogen atoms, a C₁₋₈ alkoxy group having one tothree halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino, aC₁₋₈ alkylamino group, a C₂₋₈ dialkylamino group, a C₂₋₈ acylaminogroup, a C₂₋₈ acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonylgroup comprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthiogroup, a C₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, orsulfamoyl;

R¹³ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkylgroup having one to three halogen atoms, or a C₁₋₃ alkyl group havingphenyl;

each of R¹⁴ and R¹⁵ independently is hydrogen, a C₁₋₈ alkyl group, aC₁₋₈ alkyl group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, or a C₁₋₃ alkyl group having phenyl;

R¹⁶ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxygroup, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈alkoxy group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, a C₂₋₈dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈ acylamino grouphaving one to three halogen atoms, a C₁₋₈ alkylsulfonylamino group,carboxyl, a C₂₋₈ acyl group, an alkoxycarbonyl group comprising a C₁₋₈alkoxy moiety, carbamoyl, a C₁₋₈ alkylthio group, a C₁₋₈ alkylsulfinylgroup, a C₁₋₈ alkylsulfonyl group, sulfamoyl, phenyl optionally havingone or more substituents, or a heterocyclic group optionally having oneor more substituents;

the ring shown below is a five-membered to eight-membered non-aromaticring optionally comprising one or two heteroatoms selected from N, S,and O, and being condensed with the benzene ring at 1- and 2-positionsof the benzene ring;

the ring shown below is an aromatic ring selected from the groupconsisting of benzene ring, naphthalene ring, thiophene ring, pyridinering, pyrimidine ring, indole ring, indazole ring, benzotriazole ring,benzisoxazole ring, benzimidazole ring, and quinoline ring; and

each of Z¹ and Z² independently is O or S.

-   (120) A diazepine derivative having the formula (Xa) described    in (119) or a pharmacologically acceptable salt thereof, wherein R¹¹    is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkyl    group having one to three halogen atoms, a halogen atom, hydroxyl,    amino, a C₁₋₈ alkylamino group, a C₂₋₈ dialkylamino group, or a C₂₋₈    acylamino group.-   (121) A diazepine derivative having the formula (Xa) described in    (119), (120), or a pharmacologically acceptable salt thereof,    wherein R¹² is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a    C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈ alkoxy    group having one to three halogen atoms, a halogen atom, hydroxyl,    nitro, cyano, amino, a C₁₋₈ alkylamino group, a C₂₋₈ dialkylamino    group, a C₂₋₈ acylamino group, or a C₂₋₈ acylamino group having one    to three halogen atoms.-   (122) A diazepine derivative having the formula (Xa) described in    one of (119) to (121) or a pharmacologically acceptable salt    thereof, wherein R¹³ is hydrogen, a C₁₋₈ alkyl group, or a C₁₋₈    alkyl group having one to three halogen atoms.-   (123) A diazepine derivative having the formula (Xa) described in    one of (119) to (122) or a pharmacologically acceptable salt    thereof, wherein each of R¹⁴ and R¹⁵ independently is hydrogen, a    C₁₋₈ alkyl group, or a C₁₋₈ alkyl group having one to three halogen    atoms.-   (124) A diazepine derivative having the formula (Xa) described in    one of (119) to (123) or a pharmacologically acceptable salt    thereof, wherein R¹⁶ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl    group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having one to three    halogen atoms, a C₁₋₈ alkoxy group having one to three halogen    atoms, a halogen atom, hydroxyl, nitro, cyano, amino, a C₁₋₈    alkylamino group, a C₂₋₈ dialkylamino group, or a heterocyclic group    optionally having one or more substituents.-   (125) A diazepine derivative having the formula (Xa) described in    one of (119) to (123) or a pharmacologically acceptable salt    thereof, wherein R¹⁶ is tetrazolyl, triazolyl, pyridyl, pyrazolyl,    oxadiazolyl, isoxazolyl, pyrrolyl, pyrrolidinyl, imidazolyl,    oxazolyl, or thiazolyl, each of which optionally has one or more    substituents selected from the group consisting of a C₁₋₈ alkyl    group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having one to three    halogen atoms, a C₁₋₈ alkoxy group having one to three halogen    atoms, a halogen atom, hydroxyl, nitro, cyano, amino, a C₁₋₈    alkylamino group, and a C₂₋₈ dialkylamino group.-   (126) A diazepine derivative having the formula (Xa) described in    one of (119) to (123) or a pharmacologically acceptable salt    thereof, wherein R¹⁶ is tetrazolyl, triazolyl, pyridyl, imidazolyl,    oxazolyl, or thiazolyl, each of which optionally has one or more    substituents selected from the group consisting of a C₁₋₈ alkyl    group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having one to three    halogen atoms, a C₁₋₈ alkoxy group having one to three halogen    atoms, a halogen atom, hydroxyl, cyano, and amino.-   (127) A diazepine derivative having the formula (Xa) described in    one of (119) to (126) or a pharmacologically acceptable salt    thereof, wherein the ring shown below is tetrahydronaphthalene,    indan, indoline, tetrahydroquinoline, or tetrahydroisoquinoline.

-   (128) A diazepine derivative having the formula (Xa) described in    one of (119) to (127) or a pharmacologically acceptable salt    thereof, wherein the ring shown below is benzene ring.

-   (129) A diazepine derivative having the formula (Xa) described in    one of (119) to (128) or a pharmacologically acceptable salt    thereof, wherein each of Z² and Z² is O.-   (130) A diazepine derivative having the following formula (Xb) or a    pharmacologically acceptable salt thereof:

wherein each of R²¹ and R²² independently is hydrogen, a C₁₋₈ alkylgroup, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl grouphaving one to three halogen atoms, a C₁₋₈ alkoxy group having one tothree halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino, aC₁₋₈ alkylamino group, a C₂₋₈ dialkylamino group, a C₂₋₈ acylaminogroup, a C₂₋₈ acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonylgroup comprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthiogroup, a C₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, orsulfamoyl;

R²³ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkylgroup having one to three halogen atoms, or a C₁₋₃ alkyl group havingphenyl;

each of R²⁴ and R²⁵ independently is hydrogen, a C₁₋₈ alkyl group, aC₁₋₈ alkyl group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, or a C₁₋₃ alkyl group having phenyl;

R²⁶ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxygroup, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈alkoxy group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, a C₂₋₈ alkylamino group, a C₂₋₈dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈ acylamino grouphaving one to three halogen atoms, a C₁₋₈ alkylsulfonylamino group,carboxyl, a C₂₋₈ acyl group, an alkoxycarbonyl group comprising a C₁₋₈alkoxy moiety, carbamoyl, a C₁₋₈ alkylthio group, a C₁₋₈ alkylsulfinylgroup, a C₁₋₈ alkylsulfonyl group, sulfamoyl, phenyl optionally havingone or more substituents, or a heterocyclic group optionally having oneor more substituents; and

p is 0 or 1.

-   (131) A diazepine derivative having the formula (Xb) described    in (130) or a pharmacologically acceptable salt thereof, wherein R²¹    is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkyl    group having one to three halogen atoms, a halogen atom, hydroxyl,    amino, a C₁₋₈ alkylamino group, a C₂₋₈ dialkylamino group, or a C₂₋₈    acylamino group.-   (132) A diazepine derivative having the formula (Xb) described in    (130), (131), or a pharmacologically acceptable salt thereof,    wherein R²² is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a    C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈ alkoxy    group having one to three halogen atoms, a halogen atom, hydroxyl,    nitro, cyano, amino, a C₁₋₈ alkylamino group, a C₂₋₈ dialkylamino    group, a C₂₋₈ acylamino group, or a C₂₋₈ acylamino group having one    to three halogen atoms.-   (133) A diazepine derivative having the formula (Xb) described in    one of (130) to (132) or a pharmacologically acceptable salt    thereof, wherein R²³ is hydrogen, a C₁₋₈ alkyl group, or a C₁₋₈    alkyl group having one to three halogen atoms.-   (134) A diazepine derivative having the formula (Xb) described in    one of (130) to (133) or a pharmacologically acceptable salt    thereof, wherein each of R²⁴ and R²⁵ independently is hydrogen, a    C₁₋₈ alkyl group, or a C₁₋₈ alkyl group having one to three halogen    atoms.-   (135) A diazepine derivative having the formula (Xb) described in    one of (130) to (134) or a pharmacologically acceptable salt    thereof, wherein R²⁶ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl    group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having one to three    halogen atoms, a C₁₋₈ alkoxy group having one to three halogen    atoms, a halogen atom, hydroxyl, nitro, cyano, amino, a C₁₋₈    alkylamino group, a C₂₋₈ dialkylamino group, or a heterocyclic group    optionally having one or more substituents.-   (136) A diazepine derivative having the formula (Xb) described in    one of (130) to (134) or a pharmacologically acceptable salt    thereof, wherein R²⁶ is tetrazolyl, triazolyl, pyridyl, pyrazolyl,    oxadiazolyl, isoxazolyl, pyrrolyl, pyrrolidinyl, imidazolyl,    oxazolyl, or thiazolyl, each of which optionally has one or more    substituents selected from the group consisting of a C₁₋₈ alkyl    group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having one to three    halogen atoms, a C₁₋₈ alkoxy group having one to three halogen    atoms, a halogen atom, hydroxyl, nitro, cyano, amino, a C₁₋₈    alkylamino group, and a C₂₋₈ dialkylamino group.-   (137) A diazepine derivative having the formula (Xb) described in    one of (130) to (133) or a pharmacologically acceptable salt    thereof, wherein R²⁶ is tetrazolyl, triazolyl, pyridyl, imidazolyl,    oxazolyl, or thiazolyl, each of which optionally has one or more    substituents selected from the group consisting of a C₁₋₈ alkyl    group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having one to three    halogen atoms, a C₁₋₈ alkoxy group having one to three halogen    atoms, a halogen atom, hydroxyl, cyano, and amino.-   (138) A diazepine derivative having the following formula (XI) or a    pharmacologically acceptable salt thereof:

wherein R¹ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈alkoxy group, a C₁₋₈ alkyl group having one to three halogen atoms, aC₁₋₈ alkoxy group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, a C₂₋₈dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈ acylamino grouphaving one to three halogen atoms, a C₁₋₈ alkylsulfonylamino group,carboxyl, a C₂₋₈ acyl group, an alkoxycarbonyl group comprising a C₁₋₈alkoxy moiety, carbamoyl, a C₁₋₈ alkylthio group, a C₁₋₈ alkylsulfinylgroup, a C₁₋₈ alkylsulfonyl group, or sulfamoyl;

R² is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkylgroup having one to three halogen atoms, or a C₁₋₃ alkyl group havingphenyl;

each of R³ and R⁴ independently is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈alkyl group having one to three halogen atoms, a halogen atom, hydroxyl,nitro, cyano, amino, or a C₁₋₃ alkyl group having phenyl;

R⁵ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxygroup, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈alkoxy group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, a C₁₋₅alkylamino group having one to five halogen atoms, a C₂₋₈ dialkylaminogroup, a C₂₋₈ acylamino group, a C₂₋₈ acylamino group having one tothree halogen atoms, a C₁₋₈ alkylsulfonylamino group, carboxyl, a C₂₋₈acyl group, an alkoxycarbonyl group comprising a C₁₋₈ alkoxy moiety,carbamoyl, a C₁₋₈ alkylthio group, a C₁₋₈ alkylsulfinyl group, a C₁₋₈alkylsulfonyl group, sulfamoyl, phenyl optionally having one or moresubstituents, or a heterocyclic group optionally having one or moresubstituents;

X is C or N;

the ring shown below is a heterocyclic ring selected from the groupconsisting of thiophene ring, pyridine ring, pyrimidine ring, quinolinering, indole ring, indoline ring, benzimidazole ring, indazole ring,benzisoxazole ring, and benzotriazole ring, and the ring is combinedwith X at the carbon atom contained in the heterocyclic ring as themember of the ring;

Z is O or S;

when X is N, Y is C═O or C═S, and the double line consisting of a solidline and a broken line is a single bond; and

when X is C, Y is N, and the double line consisting of a solid line anda broken line is a double bond.

-   (139) A diazepine derivative having the formula (XI) described    in (138) or a pharmacologically acceptable salt thereof, wherein R¹    is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl    group having one to three halogen atoms, a C₁₋₈ alkoxy group having    one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano,    amino, a C₁₋₈ alkylamino group, a C₂₋₈ dialkylamino group, a C₂₋₈    acylamino group, or a C₂₋₈ acylamino group having one to three    halogen atoms.-   (140) A diazepine derivative having the formula (XI) described in    (138), (139), or a pharmacologically acceptable salt thereof,    wherein R² is hydrogen, a C₁₋₈ alkyl group, or a C₁₋₈ alkyl group    having one to three halogen atoms.-   (141) A diazepine derivative having the formula (XI) described in    one of (138) to (140) or a pharmacologically acceptable salt    thereof, wherein each of R³ and R⁴ independently is hydrogen, a C₁₋₈    alkyl group, or a C₁₋₈ alkyl group having one to three halogen    atoms.-   (142) A diazepine derivative having the formula (XI) described in    one of (138) to (141) or a pharmacologically acceptable salt    thereof, wherein R⁵ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl    group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having one to three    halogen atoms, a C₁₋₈ alkoxy group having one to three halogen    atoms, a halogen atom, hydroxyl, nitro, cyano, amino, a C₁₋₈    alkylamino group, a C₂₋₈ dialkylamino group, or a heterocyclic group    optionally having one or more substituents.-   (143) A diazepine derivative having the formula (XI) described in    one of (138) to (141) or a pharmacologically acceptable salt    thereof, wherein R⁵ is tetrazolyl, triazolyl, imidazolyl, oxazolyl,    or thiazolyl, each of which optionally has one or more substituents    selected from the group consisting of a C₁₋₈ alkyl group, a C₁₋₈    alkoxy group, a C₁₋₈ alkyl group having one to three halogen atoms,    a C₁₋₈ alkoxy group having one to three halogen atoms, a halogen    atom, hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, and a    C₂₋₈ dialkylamino group.-   (144) A diazepine derivative having the formula (XI) described in    one of (138) to (141) or a pharmacologically acceptable salt    thereof, wherein R⁵ is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy    group, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈    alkoxy group having one to three halogen atoms, or hydroxyl.-   (145) A diazepine derivative having the formula (XI) described in    one of (138) to (144) or a pharmacologically acceptable salt    thereof, wherein Z is O.-   (146) A diazepine derivative having the following formula (XIa) or a    pharmacologically acceptable salt thereof:

wherein R¹¹ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, aC₁₋₈ alkoxy group, a C₁₋₈ alkyl group having one to three halogen atoms,a C₁₋₈ alkoxy group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, a C₂₋₈dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈ acylamino grouphaving one to three halogen atoms, a C₁₋₈ alkylsulfonylamino group,carboxyl, a C₂₋₈ acyl group, an alkoxycarbonyl group comprising a C₁₋₈alkoxy moiety, carbamoyl, a C₁₋₈ alkylthio group, a C₁₋₈ alkylsulfinylgroup, a C₁₋₈ alkylsulfonyl group, or sulfamoyl;

each of R¹³ and R¹⁴ independently is hydrogen, a C₁₋₈ alkyl group, aC₁₋₈ alkyl group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, or a C₁₋₃ alkyl group having phenyl;

R¹⁵ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxygroup, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈alkoxy group having one to three halogen atoms, a halogen atom,hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, a C₁₋₅alkylamino group having one to five halogen atoms, a C₂₋₈ dialkylaminogroup, a C₂₋₈ acylamino group, a C₂₋₈ acylamino group having one tothree halogen atoms, a C₁₋₈ alkylsulfonylamino group, carboxyl, a C₂₋₈acyl group, an alkoxycarbonyl group comprising a C₁₋₈ alkoxy moiety,carbamoyl, a C₁₋₈ alkylthio group, a C₁₋₈ alkylsulfinyl group, a C₁₋₈alkylsulfonyl group, sulfamoyl, phenyl optionally having one or moresubstituents, or a heterocyclic group optionally having one or moresubstituents; and

the ring shown below is a heterocyclic ring selected from the groupconsisting of thiophene ring, pyridine ring, pyrimidine ring, quinolinering, indole ring, indoline ring, benzimidazole ring, indazole ring,benzisoxazole ring, and benzotriazole ring, and the ring is combinedwith X at the carbon atom contained in the heterocyclic ring as themember of the ring.

-   (147) A diazepine derivative having the formula (XIa) described    in (146) or a pharmacologically acceptable salt thereof, wherein R¹¹    is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl    group having one to three halogen atoms, a C₁₋₈ alkoxy group having    one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano,    amino, a C₁₋₈ alkylamino group, a C₂₋₈ dialkylamino group, a C₂₋₈    acylamino group, or a C₂₋₈ acylamino group having one to three    halogen atoms.-   (148) A diazepine derivative having the formula (XIa) described    in (146) or a pharmacologically acceptable salt thereof, wherein R¹¹    is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl    group having one to three halogen atoms, a C₁₋₈ alkoxy group having    one to three halogen atoms, or a halogen atom.-   (149) A diazepine derivative having the formula (XIa) described in    one of (146) to (148) or a pharmacologically acceptable salt    thereof, wherein each of R¹³ and R¹⁴ independently is hydrogen, a    C₁₋₈ alkyl group, or a C₁₋₈ alkyl group having one to three halogen    atoms.-   (150) A diazepine derivative having the formula (XIa) described in    one of (146) to (149) or a pharmacologically acceptable salt    thereof, wherein R¹⁵ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl    group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having one to three    halogen atoms, a C₁₋₈ alkoxy group having one to three halogen    atoms, a halogen atom, hydroxyl, nitro, cyano, amino, a C₁₋₈    alkylamino group, a C₂₋₈ dialkylamino group, or a heterocyclic group    optionally having one or more substituents.-   (151) A diazepine derivative having the formula (XIa) described in    one of (146) to (149) or a pharmacologically acceptable salt    thereof, wherein R¹⁵ is tetrazolyl, triazolyl, imidazolyl, oxazolyl,    or thiazolyl, each of which optionally has one or more substituents    selected from the group consisting of a C₁₋₈ alkyl group, a C₁₋₈    alkoxy group, a C₁₋₈ alkyl group having one to three halogen atoms,    a C₁₋₈ alkoxy group having one to three halogen atoms, a halogen    atom, hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, and a    C₂₋₈ dialkylamino group.-   (152) A diazepine derivative having the formula (XIa) described in    one of (146) to (149) or a pharmacologically acceptable salt    thereof, wherein R¹⁵ is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy    group, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈    alkoxy group having one to three halogen atoms or hydroxyl.-   (153) A compound having the following formula (XII) or a    pharmacologically acceptable salt thereof:

wherein each of R¹ and R² independently is hydrogen, a C₁₋₈ alkyl group,a C₂₋₈ alkenyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having oneto three halogen atoms, a C₁₋₈ alkoxy group having one to three halogenatoms, an aralkyl group comprising a C₆₋₁₀ aryl moiety and a C₁₋₃alkylene moiety, a halogen atom, hydroxyl, nitro, cyano, amino, a C₁₋₈alkylamino group, a C₂₋₈ dialkylamino group, a C₂₋₈ acylamino group, aC₂₋₈ acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonylgroup comprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthiogroup, a C₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, orsulfamoyl;

R³ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkylgroup having one to three halogen atoms, or an aralkyl group comprisinga C₆₋₁₀ aryl moiety and a C₁₋₃ alkylene moiety;

R⁴ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxygroup, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈alkoxy group having one to three halogen atoms, an aralkyl groupcomprising a C₆₋₁₀ aryl moiety and a C₁₋₃ alkylene moiety, a C₁₋₈ alkylgroup having hydroxyl, a halogen atom, hydroxyl, nitro, cyano, amino, aC₁₋₈ alkylamino group, a C₁₋₅ alkylamino group having one to fivehalogen atoms, a C₂₋₈ dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, benzenesulfonylamino optionally having one ormore substituents, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonyl groupcomprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthio group, aC₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, sulfamoyl, phenyloptionally having one or more substituents, or a heterocyclic groupoptionally having one or more substituents;

the ring shown below is a five-membered to eight-membered ringoptionally comprising one or more heteroatoms selected from N, S, and Oas the members of the ring, and being condensed with the benzene ring at1- and 2-positions of the benzene ring; and

the ring shown below is an aromatic ring selected from the groupconsisting of benzene ring, naphthalene ring, pyridine ring, pyrimidinering, quinoline ring, indole ring, indoline ring, benzimidazole ring,indazole ring, benzisoxazole ring, and benzotriazole ring.

-   (154) A compound having the formula (XII) described in (153) or a    pharmacologically acceptable salt thereof, wherein each of R¹ and R²    independently is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group,    a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈ alkoxy    group having one to three halogen atoms, a halogen atom, hydroxyl,    nitro, cyano, or amino.-   (155) A compound having the formula (XII) described in (153), (154),    or a pharmacologically acceptable salt thereof, wherein R³ is    hydrogen or a C₁₋₈ alkyl group.-   (156) A compound having the formula (XII) described in one of (153)    to (155) or a pharmacologically acceptable salt thereof, wherein R⁴    is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl    group having one to three halogen atoms, a C₁₋₈ alkoxy group having    one to three halogen atoms, a C₁₋₈ alkyl group having hydroxyl, a    halogen atom, hydroxyl, cyano, amino, a C₁₋₈ alkylamino group, a    C₂₋₈ dialkylamino group, a C₁₋₈ alkylsulfonylamino group,    benzenesulfonylamino optionally having one or more substituents,    phenyl optionally having one or more substituents, or a heterocyclic    group optionally having one or more substituents.-   (157) A compound having the formula (XII) described in one of (153)    to (155) or a pharmacologically acceptable salt thereof, wherein R⁴    is tetrazolyl, triazolyl, pyridyl, imidazolyl, oxazolyl, or    triazolyl, each of which optionally has one or more substituents    selected from the group consisting of a C₁₋₈ alkyl group, a C₁₋₈    alkoxy group, a C₁₋₈ alkyl group having one to three halogen atoms,    a C₁₋₈ alkoxy group having one to three halogen atoms, a halogen    atom, hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, and a    C₂₋₈ dialkylamino group.-   (158) A compound having the formula (XII) described in one of (153)    to (155) or a pharmacologically acceptable salt thereof, wherein R⁴    is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl    group having one to three halogen atoms, a C₁₋₈ alkoxy group having    one to three halogen atoms, a halogen atom, hydroxyl, cyano, amino,    a C₁₋₈ alkylamino group, a C₂₋₈ dialkylamino group, or    benzenesulfonylamino optionally having one or more substituents    selected from the group consisting of a C₁₋₈ alkyl group, a C₁₋₈    alkoxy group, a halogen atom, and nitro.-   (159) A compound having the formula (XII) described in one of (153)    to (158) or a pharmacologically acceptable salt thereof, wherein the    ring shown below is naphthalene ring, tetrahydronaphthalene ring, or    indan ring.

-   (160) A compound having the formula (XII) described in one of (153)    to (159) or a pharmacologically acceptable salt thereof, wherein the    ring shown below is benzene ring or indole ring.

-   (161) A compound having the following formula (XIIa) or a    pharmacologically acceptable salt thereof:

wherein each of R¹¹ and R¹² independently is hydrogen, a C₁₋₈ alkylgroup, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl grouphaving one to three halogen atoms, a C₁₋₈ alkoxy group having one tothree halogen atoms, an aralkyl group comprising a C₆₋₁₀ aryl moiety anda C₁₋₃ alkylene moiety, a halogen atom, hydroxyl, nitro, cyano, amino, aC₁₋₈ alkylamino group, a C₂₋₈ dialkylamino group, a C₂₋₈ acylaminogroup, a C₂₋₈ acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonylgroup comprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthiogroup, a C₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, orsulfamoyl;

R¹³ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkylgroup having one to three halogen atoms, or an aralkyl group comprisinga C₆₋₁₀ aryl moiety and a C₁₋₃ alkylene moiety;

R¹⁴ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxygroup, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈alkoxy group having one to three halogen atoms, an aralkyl groupcomprising a C₆₋₁₀ aryl moiety and a C₁₋₃ alkylene moiety, a C₁₋₈ alkylgroup having hydroxyl, a halogen atom, hydroxyl, nitro, cyano, amino, aC₁₋₈ alkylamino group, a C₁₋₅ alkylamino group having one to fivehalogen atoms, a C₂₋₈ dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, benzenesulfonylamino optionally having one ormore substituents, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonyl groupcomprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthio group, aC₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, sulfamoyl, phenyloptionally having one or more substituents, or a heterocyclic groupoptionally having one or more substituents; and

the ring shown below is naphthalene ring, tetrahydronaphthalene ring, orindan ring.

-   (162) A compound having the formula (XIIa) described in (161) or a    pharmacologically acceptable salt thereof, wherein each of R¹¹ and    R¹² independently is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy    group, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈    alkoxy group having one to three halogen atoms, a halogen atom,    hydroxyl, nitro, cyano, or amino.-   (163) A compound having the formula (XIIa) described in (161), (162)    or a pharmacologically acceptable salt thereof, wherein R¹³ is    hydrogen or a C₁₋₈ alkyl group.-   (164) A compound having the formula (XIIa) described in one of (161)    to (163) or a pharmacologically acceptable salt thereof, wherein R¹⁴    is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl    group having one to three halogen atoms, a C₁₋₈ alkoxy group having    one to three halogen atoms, a C₁₋₈ alkyl group having hydroxyl, a    halogen atom, hydroxyl, cyano, amino, a C₁₋₈ alkylamino group, a    C₂₋₈ dialkylamino group, a C₁₋₈ alkylsulfonylamino group,    benzenesulfonylamino optionally having one or more substituents,    phenyl optionally having one or more substituents, or a heterocyclic    group optionally having one or more substituents.-   (165) A compound having the formula (XIIa) described in one of (161)    to (163) or a pharmacologically acceptable salt thereof, wherein R¹⁴    is tetrazolyl, triazolyl, pyridyl, imidazolyl, oxazolyl, or    triazolyl, each of which optionally has one or more substituents    selected from the group consisting of a C₁₋₈ alkyl group, a C₁₋₈    alkoxy group, a C₁₋₈ alkyl group having one to three halogen atoms,    a C₁₋₈ alkoxy group having one to three halogen atoms, a halogen    atom, hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, and a    C₂₋₈ dialkylamino group.-   (166) A compound having the formula (XIIa) described in one of (161)    to (163) or a pharmacologically acceptable salt thereof, wherein R¹⁴    is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl    group having one to three halogen atoms, a C₁₋₈ alkoxy group having    one to three halogen atoms, a halogen atom, hydroxyl, cyano, amino,    a C₁₋₈ alkylamino group, a C₂₋₈ dialkylamino group, or    benzenesulfonylamino optionally having one or more substituents    selected from the group consisting of a C₁₋₈ alkyl group, a C₁₋₈    alkoxy group, a halogen atom, and nitro.-   (167) A compound having the formula (XIIa) described in one of (161)    to (166) or a pharmacologically acceptable salt thereof, wherein the    ring shown below is naphthalene ring.

-   (168) A compound having the formula (XIIa) described in (161) or a    pharmacologically acceptable salt thereof, wherein R¹¹, R¹², R¹³,    and the ring shown below are the same as those defined in (161), and    R¹⁴ is NHSO₂R, wherein R is an aryl group optionally having one or    more substituents or a heterocyclic group optionally having one or    more substituents.

-   (169) A compound having the formula (XIIa) described in (168) or a    pharmacologically acceptable salt thereof, wherein R is phenyl,    naphthyl, quinolyl, pyridyl, or thienyl, which of which optionally    has one or more substituents, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy    group, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈    alkoxy group having one to three halogen atoms, hydroxyl, amino,    nitro, or a halogen atom.-   (170) A compound having the following formula (XIII) or a    pharmacologically acceptable salt thereof:

wherein each of R¹ and R² independently is hydrogen, a C₁₋₈ alkyl group,a C₂₋₈ alkenyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having oneto three halogen atoms, a C₁₋₈ alkoxy group having one to three halogenatoms, an aralkyl group comprising a C₆₋₁₀ aryl moiety and a C₁₋₃alkylene moiety, a halogen atom, hydroxyl, nitro, cyano, amino, a C₁₋₈alkylamino group, a C₂₋₈ dialkylamino group, a C₂₋₈ acylamino group, aC₂₋₈ acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonylgroup comprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthiogroup, a C₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, orsulfamoyl;

R³ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkylgroup having one to three halogen atoms, or an aralkyl group comprisinga C₆₋₁₀ aryl moiety and a C₁₋₃ alkylene moiety;

R⁴ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxygroup, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈alkoxy group having one to three halogen atoms, an aralkyl groupcomprising a C₆₋₁₀ aryl moiety and a C₁₋₃ alkylene moiety, a C₁₋₈ alkylgroup having hydroxyl, a halogen atom, hydroxyl, nitro, cyano, amino, aC₁₋₈ alkylamino group, a C₁₋₅ alkylamino group having one to fivehalogen atoms, a C₂₋₈ dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, benzenesulfonylamino optionally having one ormore substituents, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonyl groupcomprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthio group, aC₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, sulfamoyl, phenyloptionally having one or more substituents, or a heterocyclic groupoptionally having one or more substituents;

the ring shown below is a five-membered to eight-membered ringoptionally comprising one or two nitrogen atoms as the members of thering, and being condensed with the benzene ring at 1- and 2-positions ofthe benzene ring; and

the ring shown below is an aromatic ring selected from the groupconsisting of benzene ring, naphthalene ring, pyridine ring, pyrimidinering, quinoline ring, indole ring, indoline ring, benzimidazole ring,pyrazole ring, indazole ring, benzisoxazole ring, and benzotriazolering;

provided that R⁴ is not hydrogen, a C₁₋₈ alkyl group, or a halogen atomin the case that the ring shown below is benzene ring.

-   (171) A compound having the formula (XIII) described in (170) or a    pharmacologically acceptable salt thereof, wherein each of R¹ and R²    independently is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group,    a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈ alkoxy    group having one to three halogen atoms, a halogen atom, hydroxyl,    nitro, cyano, or amino.-   (172) A compound having the formula (XIII) described in (170),    (171), or a pharmacologically acceptable salt thereof, wherein R³ is    hydrogen or a C₁₋₈ alkyl group.-   (173) A compound having the formula (XIII) described in one of (170)    to (172) or a pharmacologically acceptable salt thereof, wherein R⁴    is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl    group having one to three halogen atoms, a C₁₋₈ alkoxy group having    one to three halogen atoms, a C₁₋₈ alkyl group having hydroxyl, a    halogen atom, hydroxyl, cyano, amino, a C₁₋₈ alkylamino group, a    C₂₋₈ dialkylamino group, a C₁₋₈ alkylsulfonylamino group,    benzenesulfonylamino optionally having one or more substituents,    phenyl optionally having one or more substituents, or a heterocyclic    group optionally having one or more substituents.-   (174) A compound having the formula (XIII) described in one of (170)    to (172) or a pharmacologically acceptable salt thereof, wherein R⁴    is tetrazolyl, triazolyl, pyridyl, imidazolyl, oxazolyl, or    triazolyl, each of which optionally has one or more substituents    selected from the group consisting of a C₁₋₈ alkyl group, a C₁₋₈    alkoxy group, a C₁₋₈ alkyl group having one to three halogen atoms,    a C₁₋₈ alkoxy group having one to three halogen atoms, a halogen    atom, hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, and a    C₂₋₈ dialkylamino group.-   (175) A compound having the formula (XIII) described in one of (170)    to (172) or a pharmacologically acceptable salt thereof, wherein R⁴    is a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having one to three    halogen atoms, a C₁₋₈ alkoxy group having one to three halogen    atoms, hydroxyl, cyano, amino, a C₁₋₈ alkylamino group, a C₂₋₈    dialkylamino group, or benzenesulfonylamino optionally having one or    more substituents selected from the group consisting of a C₁₋₈ alkyl    group, a C₁₋₈ alkoxy group, a halogen atom, and nitro.-   (176) A compound having the formula (XIII) described in one of (170)    to (175) or a pharmacologically acceptable salt thereof, wherein the    ring shown below is naphthalene ring, tetrahydronaphthalene ring, or    indan ring.

-   (177) A compound having the formula (XIII) described in one of (170)    to (176) or a pharmacologically acceptable salt thereof, wherein the    ring shown below is benzene ring or indole ring.

-   (178) A compound having the following formula (XIIIa) or a    pharmacologically acceptable salt thereof:

wherein each of R¹¹ and R¹² independently is hydrogen, a C₁₋₈ alkylgroup, a C₂₋₈ alkenyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl grouphaving one to three halogen atoms, a C₁₋₈ alkoxy group having one tothree halogen atoms, an aralkyl group comprising a C₆₋₁₀ aryl moiety anda C₁₋₃ alkylene moiety, a halogen atom, hydroxyl, nitro, cyano, amino, aC₂₋₈ alkylamino group, a C₂₋₈ dialkylamino group, a C₂₋₈ acylaminogroup, a C₂₋₈ acylamino group having one to three halogen atoms, a C₁₋₈alkylsulfonylamino group, carboxyl, a C₂₋₈ acyl group, an alkoxycarbonylgroup comprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈ alkylthiogroup, a C₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group, orsulfamoyl;

R¹³ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈ alkylgroup having one to three halogen atoms, or an aralkyl group comprisinga C₆₋₁₀ aryl moiety and a C₁₋₃ alkylene moiety;

R¹⁴ is a C₂₋₈ alkenyl group, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl grouphaving one to three halogen atoms, a C₁₋₈ alkoxy group having one tothree halogen atoms, an aralkyl group comprising a C₆₋₁₀ aryl moiety anda C₁₋₃ alkylene moiety, a C₁₋₈ alkyl group having hydroxyl, hydroxyl,nitro, cyano, amino, a C₁₋₈ alkylamino group, a C₁₋₅ alkylamino grouphaving one to five halogen atoms, a C₂₋₈ dialkylamino group, a C₂₋₈acylamino group, a C₂₋₈ acylamino group having one to three halogenatoms, a C₁₋₈ alkylsulfonylamino group, benzenesulfonylamino optionallyhaving one or more substituents, carboxyl, a C₂₋₈ acyl group, analkoxycarbonyl group comprising a C₁₋₈ alkoxy moiety, carbamoyl, a C₁₋₈alkylthio group, a C₁₋₈ alkylsulfinyl group, a C₁₋₈ alkylsulfonyl group,sulfamoyl, phenyl optionally having one or more substituents, or aheterocyclic group optionally having one or more substituents; and

the ring shown below is naphthalene ring, tetrahydronaphthalene ring, orindan ring.

-   (179) A compound having the formula (XIIIa) described in (178) or a    pharmacologically acceptable salt thereof, wherein each of R¹¹ and    R¹² independently is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkoxy    group, a C₁₋₈ alkyl group having one to three halogen atoms, a C₁₋₈    alkoxy group having one to three halogen atoms, a halogen atom,    hydroxyl, nitro, cyano, or amino.-   (180) A compound having the formula (XIIIa) described in (178),    (179), or a pharmacologically acceptable salt thereof, wherein R¹³    is hydrogen.-   (181) A compound having the formula (XIIIa) described in one    of (178) to (180) or a pharmacologically acceptable salt thereof,    wherein R¹⁴ is a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having one to    three halogen atoms, a C₁₋₈ alkoxy group having one to three halogen    atoms, a C₁₋₈ alkyl group having hydroxyl, hydroxyl, cyano, amino, a    C₁₋₈ alkylamino group, a C₂₋₈ dialkylamino group, a C₁₋₈    alkylsulfonylamino group, benzenesulfonylamino optionally having one    or more substituents, phenyl optionally having one or more    substituents, or a heterocyclic group optionally having one or more    substituents.-   (182) A compound having the formula (XIIIa) described in one    of (178) to (180) or a pharmacologically acceptable salt thereof,    wherein R¹⁴ is tetrazolyl, triazolyl, pyridyl, imidazolyl, oxazolyl,    or triazolyl, each of which optionally has one or more substituents    selected from the group consisting of a C₁₋₈ alkyl group, a C₁₋₈    alkoxy group, a C₁₋₈ alkyl group having one to three halogen atoms,    a C₁₋₈ alkoxy group having one to three halogen atoms, a halogen    atom, hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, and a    C₂₋₈ dialkylamino group.-   (183) A compound having the formula (XIIIa) described in one    of (178) to (180) or a pharmacologically acceptable salt thereof,    wherein R¹⁴ is a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having one to    three halogen atoms, a C₁₋₈ alkoxy group having one to three halogen    atoms, hydroxyl, cyano, amino, a C₁₋₈ alkylamino group, a C₂₋₈    dialkylamino group, or benzenesulfonylamino optionally having one or    more substituents selected from the group consisting of a C₁₋₈ alkyl    group, a C₁₋₈ alkoxy group, a halogen atom, and nitro.-   (184) A compound having the formula (XIIIa) described in one    of (178) to (183) or a pharmacologically acceptable salt thereof,    wherein the ring shown below is naphthalene ring.

-   (185)    5-[3-(1H-tetrazole-5-yl)phenyl]-8,9,10,11-tetrahydronaphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione    sodium salt,-   5-(1H-indol-6-yl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione,-   4-[3-(1H-tetrazole-5-yl)phenyl]-1,4-dihydrobenzo[f]quinoxaline-2,3-dione    sodium salt, or-   4-[3-(1H-tetrazole-5-yl)phenyl]-1H-benzo[h]quinazolin-2-one sodium    salt.

The above-mentioned compounds can be prepared according to knownprocesses. For example, the compounds described in (2) to (4) can beprepared according to a process described in WO 2004/085440. Thecompounds described in (5) and (117) can be prepared according to aprocess described in Japanese Patent Publication No. 59 (1984)-48826.The compounds described in (8) to (16) can be prepared according to aprocess described in WO 2007/072974. The compounds described in (17) to(36) can be prepared according to a process described in WO 2007/074970.The compounds described in (37) to (52) can be prepared according to aprocess described in WO 2008/023847. The compounds described in (53) to(79) can be prepared according to a process described in WO 2009/022730.The compounds described in (80) to (94) can be prepared according to aprocess described in WO 2009/022731. The compounds described in (95) to(102) can be prepared according to a process described in WO2010/090300. The compounds described in (103) to (116) can be preparedaccording to a process described in WO 2010/093061.

The compounds described in (7) and (117) such as paroxetine, imipramineare known compounds. The chemical structures and the documentsdisclosing the processes for preparation of the compounds are describedin The MERCK INDEX FOURTEENTH EDITION (2006) or the like. Further, thesecompounds are commercially available.

The selective serotonin reuptake inhibitors described in (6) includeparoxetine, fluoxetine, fluvoxamine, and citalopram.

The above-mentioned WO 2004/085440, WO 2007/072974, WO 2007/074970, WO2008/023847, WO 2009/022730, WO 2009/022731, WO 2010/090300, WO2010/093061, WO 2007/049825, and WO 2008/020651 describe that thecompounds described in (2) to (117) have P2X₄ receptor antagonism.

The compounds described in (118) to (185) also have P2X4 receptorantagonism, and can be prepared according to the processes described inthe documents cited in the processes for preparation of the compoundsdescribed in (2) to (5) and (8) to (116).

The pharmacologically acceptable salts in the active ingredients of thepresent invention include a salt with an acid (e.g., as hydrochloricacid, acetic acid, benzoic acid, fumaric acid, besylic acid), an alkalimetal (e.g., sodium, potassium, lithium), or an amine.

The active ingredients of the present invention can be a geometrical(cis-trans) isomer or an optical isomer such as an optically activesubstance and racemic modification, each of which is included within thescope of the invention. Hydrates can also be used as the activeingredients of the present invention.

The results of the pharmacological experiments are described below.

The effect of P2X₄ receptor antagonist on herpes zoster-associated painin acute phase was examined using a mouse model (Examples 3 and 4).

The results of Examples 3 and 4 as well as FIGS. 4 and 5 show analgesicactivities of paroxetine and the compound A(5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dionesodium salt), which have P2X₄ receptor antagonism, on an acute phase ofherpes zoster-induced pain. The results suggest that P2X₄ receptor playsa major role in the acute phase of herpes zoster-induced pain.

Further, immunohistological analysis and real time RT-PCR analysis usingthe mouse model of herpes zoster show that spinal microglial cellsproliferate in the acute phase of herpes zoster, and that expression ofP2X₄ receptor is increased in activated microglia. The results suggestthat, in acute phase of the herpes zoster, spinal microglia becomeactivated with proliferation and increase expression of P2X₄ receptors(Example 2, FIGS. 1-3). Accordingly, proliferation and activation ofmicroglia and P2X₄ receptor with development of the syndrome of theherpes zoster in acute phase play important roles in causing the acutephase pain by herpes zoster. Therefore, it is suggested that P2X₄receptor antagonist can be an effective therapeutic agent for acutephase pain of herpes zoster.

Aciclovir, Valaciclovir, and Famciclovir are conventional anti-herpeticdrugs and have been used for treating herpes zoster in acute phase. Ithas been reported that they have an effect of accelerating healingexanthema and may shorten the duration of the zoster-associated pain(Wood M J, et al., Clin Infect Dis, 1996, 22:341-347; Beutner K R, etal., Antimicrob Agents Chemother, 1995, 39:1546-1553; Tyring SK., SeminDermatol, 1996, 15:27-31; Wood M J, et al., N Engl J Med, 1994,330:896-900; Rowbotham M C., Semin Nuerol, 1994, 14:247-254; Wood M J,et al., Am J Med, 1988, 85:79-83; Huff J C, et al., Am J Med, 1988,85:84-89; and McKendrick M W, et al., BMJ, 1989, 298:431). It has alsobeen suggested that continuous desensitization is necessary forpreventing acute phase pain of herpes zoster from changing intopostherpetic neuralgia (Manabe et al., Clin J Pain, 1995, 11:220-228).Therefore, it is suggested that combinations of the above-mentioneddrugs with the P2X₄ receptor antagonist may show a stronger analgesicactivity by removing acute phase pain to prevent or treat thepostherpetic neuralgia.

The preventive or therapeutic agent of the present invention can beadministered to human beings by ordinary administration methods such asoral administration or parenteral administration.

The compound can be granulated in ordinary manners for the preparationof pharmaceuticals. For instance, the compound can be processed to givetablets, granule, powder, capsule, suspension, injection, suppository,and the like.

Ordinary additives such as vehicles, disintegrators, binders,lubricants, dyes, and diluents are used for the preparation of thesepharmaceuticals such as tablets. As the vehicles, lactose, D-mannitol,crystalline cellulose, and glucose can be mentioned. Further, there canbe mentioned starch and carboxymethylcellulose calcium (CMC-Ca) as thedisintegrators, magnesium stearate and talc as the lubricants, andhydroxylpropylcellulose (HPC), gelatin and polyvinylpyrrolidone (PVP) asthe binders. The preparation of an injection can be made using solvents,stabilizers, dissolution-aids, suspensions, emulsifiers, soothingagents, buffers, or preservatives.

The compound of the invention can be administered to an adult generallyin an amount of approximately 0.01 mg to 100 mg a day by parenteraladministration and 1 mg to 2,000 mg a day by oral administration. Thedosage can be adjusted in consideration of age and conditions of thepatient.

EXAMPLES Example 1

(Experimental Procedure)

P2X₄ receptor antagonisms of the compound A(5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dionesodium salt; described in Example 14 of WO 2010/093061) and paroxetinewere measured as described below.

ATP receptors (human P2X₄) were introduced into 1321N1 cells, and usedas a stable ATP receptor-expressing system. The obtained P2X₄ expressing1321N1 cells were plated in a 96-well assay plate, and cultured 24 hoursat 37° C. in an atmosphere of 5% CO₂ for calcium assay. Fura-2 AMcalcium fluorescent indicator was dissolved in an extracellular solutionfor calcium imaging. The obtained solution was loaded onto the platedcells, and placed at room temperature for 45 minutes to introduce Fura-2AM into the cells. The fluorescence was detected by FLUOstar OPTIMAmicro plate reader (BMG Lab-tech). The cells were alternativelyilluminated with two excitations wavelengths (340 nm and 380 nm) viaxenon lamp, and the emitted fluorescence was measured at 510 nm. Thefluorescence changes after the treatment of 1 μM ATP were monitored anddetermined the fluorescence ratio (F340/F380) as the index ofintracellular calcium change. Tested compounds were treated to cells 15min before the addition of ATP, and the inhibitory activities ofcompounds were calculated by comparing the Ca2+ response with control inthe absence of tested compound.

(Experimental Results)

TABLE 1 Test compound IC₅₀ (μM) Paroxetine 4.6 Compound A 0.27

Example 2

Immunohistological and RT-real time PCR analyses were conducted usingthe mouse model of herpes zoster to study that spinal microglia cellsproliferate in acute phase of herpes zoster, and expression of P2X₄receptor increases in activated microglia.

(Experimental Procedure)

Epidermis of the right hind leg (lower part of knee joint) of shavenfemale C57BL/6J mice was chopped with a bundle of ten 26G injectionneedles, and coated with a solution (1×10⁶ pfu/site) of herpes simplexvirus Type I (HSV-1), which as well as varicella zoster virus, belongsto Herpesviridae (family) (Takasaki I, et al., Anesthesiology, 2002,96:1168-1174). Seven days after infection, the spinal cord was collectedafter perfusion of 4% neutral buffered paraformaldehyde, replaced with30% sucrose solution, embedded with OCT compound to prepare frozenslices. A specimen in cross section was prepared at the fifth lumbarlevel of the spinal cord, and was subjected to a fluorescent doubleimmunostaining according to Alexa Fluor 488, 546 using OX42 antibody,which has widely been used as a microglia marker, and P2X₄ receptorantibody.

(Experimental Results)

The obtained fluorescent immunostaining images are shown in FIG. 1.Seven days after infection, immunofluorescence intensities of OX42(microglia marker) and P2X₄ receptor increase on the side treated withHSV-1 (right figures) within L5 segment of the spinal cord, comparedwith the side with no HSV-1 treatment (left figures). Further, it isobserved that the two signals are co-localized clearly (the areaindicated by the arrow in the upper right figure and the area circledwith the dotted line in the lower right figure).

The results of RT-real time PCR analysis of the herpes zostermanifestation are shown in FIG. 2. Mice were infected with HSV-1 tocause manifestation of herpes zoster. The total RNA was extracted fromthe L5 segment of the spinal cord from third day to twentieth day in theacute phase, and subjected to a reverse transcription to obtain cDNA.The changes in mRNA expression of Iba1, which is a calcium-bindingprotein with microglia-specific expression, and P2X₄ receptor wasstudied using a Taq Man real time PCR method. The Iba1 mRNA expressionwas significantly increased from five days to twenty days afterinfection, and the increase peaked at day seven (FIG. 2). With respectto P2X₄ receptor, a peak was also observed seven days after infection,and significant increase was observed from five days to fifteen daysafter infection (FIG. 3). As is evident from the results, thetime-course of the increase in mRNA expressions of Iba1 (microgliamarker) and P2X₄ receptor was almost same. Taken these results together,it is suggested that the expression of P2X₄ receptors in the spinal cordis increased in the proliferated microglia that occurs in the acutephase of herpes zoster.

Example 3

(Experimental Procedure)

The effect of P2X₄ receptor antagonist in zoster-associated pain inacute phase was studied using the mouse model of herpes zoster describedin Example 2. At seven days after infection corresponding to the time ofzoster-associated pain in acute phase and thirty days after infectioncorresponding to the time of postherpetic neuralgia, paroxetine (30mg/kg, 50 mg/kg) or the solvent (tap water) was orally administered. Ithas been reported that paroxetine functions as an inhibitor of P2X₄receptor (Nagata K, Imai T et al., Molecular Pain, 2009, 5:20). Thepain-associated reaction of the hindpaw on the HSV-1 infection side wasmeasured and evaluated referring to the response to a contact stimulantusing a paint-brush. The mouse was placed into a cage for measurement,and accustomed to the environment for 1 hour or more. The plantarsurface of the right hindpaw was vertically stroked with the paintbrushalong the direction from toe to heal, and this was repeated six times atintervals of several seconds. The pain reaction was evaluated asfollows:

-   Score 0: No reaction-   Score 1: Lifting of hind leg-   Score 2: Sharp evasion reaction and flinching of hind leg

Each individual pain score was calculated by averaging six scores.

(Experimental Results)

FIG. 4 shows influence of oral administration of paroxetine on acutephase pain of herpes zoster. Mice were inoculated with HSV-1, and thepain score reached the almost maximum seven days after infection. Sevendays after infection, threshold of the pain was significantly improvedfrom 1 hour to 4 hours after administration of paroxetine (30 mg/kg)into the mice. In the group of administration of 50 mg/kg of paroxetine,it was observed that threshold of the pain was continuously improvedfrom 30 minutes to 8 hours after administration (the right figure ofFIG. 4). Thirty days after infection, 30 mg/kg of paroxetine did notshow any significant improvement on the threshold of the pain, and onlyin the group of 50 mg/kg of paroxetine, significant improvement wasobserved on the threshold of the pain 30 minutes, 1 hour, and 4 hoursafter administration (the left figure of FIG. 4).

Example 4

(Experimental Procedure)

The effect of P2X₄ receptor antagonism on zoster-associated pain inacute phase was studied using the mouse model of herpes zoster describedin Example 2. From five days to seven days after infection correspondingto the time of zoster-associated pain in acute phase, the compound A (10pmol/mouse, 30 pmol/mouse), which is a P2X₄ receptor-specificantagonist, or PBS was intrathecally administered twice a day, at AM10:00 to 11:00 and PM 6:00 to 7:00. Threshold of the pain was measuredbefore administration of the drug (AM 9:30 to 10:00 and PM 5:30 to6:00). Pain-associated reaction on the HSV-1 infection side hindpaw wasmeasured using von Frey Filament (0.16 g). The mouse was placed into acage for measurement, and accustomed to the environment for 1 hour ormore. The von Frey filament was vertically applied to the right hindpawfor three to five seconds to bend the filament slightly, and this wasrepeated six times at intervals of several seconds. The pain reactionwas evaluated as follows:

-   Score 0: No reaction-   Score 1: Lifting of hind leg-   Score 2: Sharp evasion reaction and flinching of hind leg

Each individual pain score was calculated by averaging six scores. Theallodynia score (%) was calculated as the average score of each group bycounting the maximum reaction score 2 as 100%.

(Experimental Results)

FIG. 5 shows the influence of intrathecal administration of the compoundA on acute phase pain of herpes zoster.

The arrow in the graph indicates the time of the intrathecaladministration of the compound A (10 pmol/mouse, 30 pmol/mouse) or PBStwice a day at AM 10:00 to 11:00 and at PM 6:00 to 7:00 after five daysto seven days after infection. Threshold of the pain was measured beforeadministration of the drugs (AM 9:30 to 10:00 and PM 5:30 to 6:00).

In the group of mice inoculated with HSV-1 and administered with PBS,the pain score reached the almost maximum seven days after infection. Inthe groups administered with 10 pmol/mouse and 30 pmol/mouse of thecompound A, it was observed that the threshold score of the pain wassignificantly suppressed compared with the pain threshold score afterthe first administration.

The invention claimed is:
 1. A method of treating prodrome or pain ofherpes zoster in acute phase comprising administrating an effectiveamount of P2X₄ receptor antagonist to a patient in need thereof.
 2. Amethod of treating prodrome or pain of herpes zoster in acute phasecomprising administrating an effective amount of a compound having thefollowing formula (IX) or a pharmacologically acceptable salt thereof toa patient in need thereof:

wherein R¹ is hydrogen, a C₁₋₈ alkyl group, a C₂₋₈ alkenyl group, a C₁₋₈alkyl group having one to three halogen atoms, or a C₁₋₃ alkyl grouphaving phenyl; each of R² and R³ independently is hydrogen, a C₁₋₈ alkylgroup, a C₁₋₈ alkoxy group, a C₁₋₈ alkyl group having one to threehalogen atoms, a C₁₋₈ alkoxy group having one to three halogen atoms, ahalogen atom, hydroxyl, nitro, cyano, amino, a C₁₋₈ alkylamino group, aC₂₋₈ dialkylamino group, a C₂₋₈ acylamino group, a C₂₋₈ acylamino grouphaving one to three halogen atoms, a C₁₋₈ alkylsulfonylamino group,carboxyl, a C₂₋₈ acyl group, an alkoxycarbonyl group comprising a C₁₋₈alkoxy moiety, carbamoyl, a C₁₋₈ alkylthio group, a C₁₋₈ alkylsulfinylgroup, a C₁₋₈ alkylsulfonyl group, or sulfamoyl; each of R⁴ and R⁵independently is hydrogen, a C₁₋₈ alkyl group, a C₁₋₈ alkyl group havingone to three halogen atoms, or a C₁₋₃ alkyl group having phenyl; and Wis a five-membered or six-membered heterocyclic ring optionally havingone or more substituents and comprising one to four nitrogen atoms asthe members of the ring.
 3. A method of treating prodrome or pain ofherpes zoster in acute phase defined in claim 2, wherein the activeingredient is5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dionesodium salt.
 4. A method of treating postherpetic neuralgia comprisingadministrating an effective amount of P2X₄ receptor antagonist to apatient of the acute phase pain of herpes zoster.
 5. A method oftreating postherpetic neuralgia comprising administrating an effectiveamount of a combination of an anti-herpetic drug with P2X₄ receptorantagonist to a patient of the acute phase pain of herpes zoster.